Mats Kalin

Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people

BACKGROUND We assessed the effectiveness of a 23-valent pneumococcal vaccine in the prevention of pneumococcal pneumonia and of pneumonia overall in non-immunocompromised middle-aged and elderly people. METHODS The prospective, multicentre, double-blind, randomised, placebo-controlled trial was carried out across departments of infectious diseases at six tertiary-care or university hospitals in Sweden. 691 non-immunocompromised patients aged 50-85 years who had been treated as inpatients for community-acquired pneumonia (CAP) were randomly assigned either 23-valent pneumococcal capsular polysaccharide vaccine or placebo (sodium chloride). We used Cox regression models to estimate the relative risks of pneumonia overall and pneumococcal pneumonia for the placebo group compared with the vaccine group. FINDINGS 63 (19%) of 339 patients in the vaccine group and 57 (16%) of 352 patients in the placebo group developed a new pneumonia, corresponding to a relative risk over time for the placebo group compared with the vaccine group of 0.83 (95% CI 0.58-1.12, p=0.31). Pneumococcal pneumonia was diagnosed in 16 (4.5%) patients in the placebo group and in 19 (5.6%) in the vaccine group, corresponding to a relative risk for the placebo group of 0.78 (95% CI 0.40-1.51, p=0.45). We found no difference in the death rate between the two study groups. INTERPRETATION The 23-valent pneumococcal polysaccharide vaccine did not prevent pneumonia overall or pneumococcal pneumonia in middle-aged and elderly individuals.

Etiology of Community-Acquired Pneumonia: Increased Microbiological Yield with New Diagnostic Methods

Abstract Background The microbial etiology of community-acquired pneumonia (CAP) is still not well characterized. During the past few years, polymerase chain reaction (PCR)-based methods have been developed for many pathogens causing respiratory tract infections. The aim of this study was to determine the etiology of CAP among adults—especially the occurrence of mixed infections among patients with CAP—by implementing a new diagnostic PCR platform combined with conventional methods. Methods Adults admitted to Karolinska University Hospital were studied prospectively during a 12-month period. Microbiological testing methods included culture from blood, sputum, and nasopharyngeal secretion samples; sputum samples analyzed by real-time quantitative PCR for Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis; nasopharyngeal specimens analyzed by use of PCR; serological testing for Mycoplasma pneumoniae, Chlamydophila pneumoniae, and viruses common in the respiratory tract; and urine antigen assays for detection of pneumococcal and Legionella pneumophila antigens. Results A microbial etiology could be identified for 67% of the patients (n = 124). For patients with complete sampling, a microbiological agent was identified for 89% of the cases. The most frequently detected pathogens were S. pneumoniae (70 patients [38]) and respiratory virus (53 patients [29]). Two or more pathogens were present in 43 (35%) of 124 cases with a determined etiology. Conclusions By supplementing traditional diagnostic methods with new PCR-based methods, a high microbial yield was achieved. This was especially evident for patients with complete sampling. Mixed infections were frequent (most commonly S. pneumoniae together with a respiratory virus).

Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies

Pneumococcus is one of the most important human pathogens that causes life-threatening invasive diseases, especially at the extremities of age. Capsular polysaccharides (CPSs) are known to induce protective antibodies; however, it is not feasible to develop CPS-based vaccines that cover all of the 90 disease-causing serotypes. We applied a genomic approach and described the antibody repertoire for pneumococcal proteins using display libraries expressing 15–150 amino acid fragments of the pathogens proteome. Serum antibodies of exposed, but not infected, individuals and convalescing patients identified the ANTIGENome of pneumococcus consisting of ∼140 antigens, many of them surface exposed. Based on several in vitro assays, 18 novel candidates were preselected for animal studies, and 4 of them showed significant protection against lethal sepsis. Two lead vaccine candidates, protein required for cell wall separation of group B streptococcus (PcsB) and serine/threonine protein kinase (StkP), were found to be exceptionally conserved among clinical isolates (>99.5% identity) and cross-protective against four different serotypes in lethal sepsis and pneumonia models, and have important nonredundant functions in bacterial multiplication based on gene deletion studies. We describe for the first time opsonophagocytic killing activity for pneumococcal protein antigens. A vaccine containing PcsB and StkP is intended for the prevention of infections caused by all serotypes of pneumococcus in the elderly and in children.

Clonal and Capsular Types Decide Whether Pneumococci Will Act as a Primary or Opportunistic Pathogen

BACKGROUND Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. The role of the different capsular and clonal types in invasive disease severity remains to be defined. METHODS Disease severity and disease type were correlated to age, underlying disease, capsular serotype, and clonal type of the causative agent for 494 adult patients with invasive pneumococcal disease. RESULTS Pneumococcal isolates of serotypes 1 and 7F were genetically homogenous, had the highest potential to infect previously healthy individuals, and were not causing deaths. Also, type 1 isolates were only found among younger adults, whereas other serotypes were mainly found among elderly persons (e.g., type 23F). Some serotypes and/or clones were more prone to cause more-severe disease, as observed by high APACHE II scores calculated at admission, and were also associated with a high mortality (e.g., clones of type 3 and 11A). We found no evidence of an impact of penicillin resistance on disease severity and disease type. CONCLUSIONS We suggest that clones with capsular types 1 and 7F, which are known to have a high invasive disease potential, behave as primary pathogens, whereas clones with other capsular types with a lower relative risk of causing invasive disease are more opportunistic, primarily affecting patients with underlying disease. Disease caused by the latter group, however, was more severe, even in previously healthy individuals.

Prospective Study of Prognostic Factors in Community-Acquired Bacteremic Pneumococcal Disease in 5 Countries

To define the influence of prognostic factors in patients with community-acquired pneumococcal bacteremia, a 2-year prospective study was performed in 5 centers in Canada, the United States, the United Kingdom, Spain, and Sweden. By multivariate analysis, the independent predictors of death among the 460 patients were age >65 years (odds ratio [OR], 2.2), living in a nursing home (OR, 2.8), presence of chronic pulmonary disease (OR, 2.5), high acute physiology score (OR for scores 9-14, 7.6; for scores 15-17, 22; and for scores >17, 41), and need for mechanical ventilation (OR, 4.4). Of patients with meningitis, 26% died. Of patients with pneumonia without meningitis, 19% of those with >/=2 lobes and 7% of those with only 1 lobe involved (P=.0016) died. The case-fatality rate differed significantly among the centers: 20% in the United States and Spain, 13% in the United Kingdom, 8% in Sweden, and 6% in Canada. Differences of disease severity and of frequencies and impact of underlying chronic conditions were factors of probable importance for different outcomes.

Dynamics of Penicillin-Susceptible Clones in Invasive Pneumococcal Disease

In a 10-year period, 1987-1997, there was a >4-fold increase in the rate of pneumococcal bacteremia in Sweden. Invasive pneumococcal isolates (n=1136), which were obtained from 18 Swedish clinical microbiology laboratories from 1987 through 1997, and other national and international isolates were serotyped, and their clonal relationships were determined by molecular typing. The increase in invasive pneumococcal disease in Sweden during this period was associated particularly with an increase in isolates of serotypes 1 and 14. A 3-fold increase of type 14 was seen from 1987 through 1992, and a 10-fold increase of type 1 occurred from 1992 through 1997. One dominating penicillin-susceptible clone of type 14 was responsible for the increase of type 14 during the first 5 years. This clone also was found in Canada and the United States and was shown by multilocus sequence typing to correspond to a previously identified hyper-virulent clone. A novel penicillin-susceptible clone of type 1, which was not found among invasive isolates from 1987 or 1992, was responsible for the increase of serotype 1 during the last 5 years. These results illustrate the ability of virulent penicillin-susceptible pneumococcal clones to emerge and spread rapidly within a country.

Molecular Epidemiology of Streptococcus pneumoniae Causing Invasive Disease in 5 Countries

A multicenter study was done during 1993-1995 to investigate prospectively the influence of several prognostic factors for predicting the risk of death among patients with pneumococcal bacteremia. Five centers located in Canada, the United Kingdom, Spain, Sweden, and the United States participated. Clinical parameters were correlated to antibiotic susceptibility and serotyping of the 354 invasive pneumococcal isolates collected and to molecular typing of 173 isolates belonging to the 5 most common serotypes (14, 9V, 23F, 3, and 7F). Serotype 14 was the most common among all isolates, but serotype 3 dominated in fatal cases and in isolates from Spain and the United States, the countries with the highest case-fatality rates. Fewer different patterns were found among the type 3 isolates, which suggests a closer clonal relationship than that among isolates belonging to other serotypes. Of type 3 isolates from fatal cases, 1 clone predominated. Other penicillin-susceptible invasive clones were also shown to spread in and between countries.

Diagnostic and prognostic value of interleukin-6 and C-reactive protein in community-acquired pneumonia.

The diagnostic and prognostic value of admission serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) was investigated in 203 hospital-treated patients with community-acquired pneumonia (CAP). In serum samples obtained during the first 24 h after admission, IL-6 was detectable in 198 patients (98%), with a median value of 50 ng/l. Ten % of the patients had IL-6 values of 1000 ng/l. A clear positive correlation between IL-6 and CRP was found (r = 0.29, p < 0.0001). Patients with high IL-6 or CRP levels had longer duration of fever, longer hospital stay, and had less often recovered clinically or radiographically on follow-up weeks after discharge. A high IL-6, but not a high CRP, also seemed to be associated with a higher mortality. Bacteremic pneumococcal pneumonia had the highest levels of IL-6 (mean 2852 and median 420 ng/l) and CRP (mean 292 and median 285 mg/l). High IL-6 values were also seen in patients with non-bacteremic pneumococcal pneumonia, while all patients with pneumonia due to other bacterial, or viral, aetiology had IL-6 levels of < or = 300 ng/l. In conclusion, IL-6 and CRP are promising diagnostic and prognostic tools in the management of CAP. Further studies are needed to establish the usefulness of repeated measurements early in the hospital course of the disease.

Bacteremic pneumococcal pneumonia in Sweden: clinical course and outcome and comparison with non-bacteremic pneumococcal and mycoplasmal pneumonias

279 patients with 285 episodes of bacteremic pneumococcal pneumonia (Pnb), treated at the 2 departments for infectious diseases in Stockholm, Sweden, were reviewed retrospectively. Almost half of all episodes were caused by serotypes 3, 9 and 4 (in that order). The overall mortality rate was 7% and as low as 5% if patients with extrapulmonary complications were excluded. As in other studies male sex, alcoholism and absence of leukocytosis on admission to hospital were all associated with a higher mortality rate. However, the prognosis for old patients was much better than in most other studies. This was true also when the infecting strain was of serotype 3. For 89 consecutive patients out of the 279 ones with Pnb the clinical, laboratory and chest X-ray data were compared with those of 44 patients with non-bacteremic pneumococcal pneumonia (Pn) and 27 patients with Mycoplasma pneumoniae pneumonia (MP). Within the pneumococcal group almost all non-bacteremic patients had respiratory tract symptoms compared to less than half of the patients with bacteremic disease. High age, alcoholism, chills, pleuritic chest pain, a leukocyte count of greater than 15 x 10(9)l and an elevated CRP were factors significantly more common among those with pneumococcal pneumonia than among the MP patients. On chest X-ray an alveolar pattern was seen in all but 2 of the totally 133 patients with a pneumococcal pneumonia, but also in half the patients with MP.

European expert opinion on the management of invasive candidiasis in adults

This report discusses the present status of antifungal therapy and treatment options for candidaemia, considered by experts in the field in Europe. A conference of 26 experts from 13 European countries was held to discuss strategies for the treatment and prevention of invasive candidiasis, with the aim of providing a review on optimal management strategies. Published and unpublished comparative trials on antifungal therapy were analysed and discussed. Commonly asked questions about the management of candidaemia were selected, and possible responses to these questions were discussed. Panellists were then asked to respond to each question by using a touchpad answering system. After the initial conference, the viewpoint document has been reviewed and edited to include new insights and developments since the initial meeting. For many situations, consensus on treatment could not be reached, and the responses indicate that treatment is likely to be modified on a patient-to-patient basis, depending on factors such as degree of illness, prior exposure to azole antifungals, and the presence of potentially antifungal drug-resistant Candida species.