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PRIORITY PRESS - 21st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Milan, Italy / May 7-10, 2011

As reported here this week, the burden of adult pneumococcal disease is significant. Not only is the incidence of invasive pneumococcal disease (IPD) increasing, but despite improvements in patient management, mortality has not improved. In adults, IPD manifests as pneumonia in 50% to 80% of cases. Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality and is brought on by a range of pathogens, of which pneumococcus is the most frequently identified in both hospitalized patients and those treated in primary care.

Treatment of IPD can be problematic, however, because causative organisms are not always identified and antibiotic-resistant pneumococci can complicate treatment decisions and cause treatment failures. Consequently, there is general agreement among experts in infectious diseases and respiratory medicine that IPD prevention through vaccination will be the most effective strategy to curb morbidity and mortality. As such, surveillance of the serotypes causing CAP and those serotypes associated with more serious clinical syndromes is important to assess the impact of pneumococcal vaccination on this important infection. New surveillance data reveal the latest trends in serotypes causing IPD in Canadian adults, while 2 new clinical studies demonstrate that a pneumococcal conjugate vaccine is at least as immunogenic as the pneumococcal polysaccharide vaccine for the 12 disease-causing serotypes common to both vaccines.

The Burden of IPD: Rising Incidence and Mortality with Age

IPD incidence in adults is increasing, reported Prof. Tobias Welte, Hannover Medical School, Germany. In Europe, for example, the incidence has risen from 13.9/100,000 adults in 1997-2001 to 19.55/100,000 adults in 2005-2007.

Despite improvements in the management of hospitalized patients with IPD, mortality remained relatively unchanged over the second half of the 20th century, hovering around 12%, noted Prof. Welte. Factors related to outcome in IPD in adults are age, S. pneumoniae site of infection, S. pneumoniae serotypes and comorbidities.The case fatality ratio for IPD increases dramatically after age 44 and continues to rise thereafter, he added, topping 40% in cases of meningitis and septicemia and reaching approximately 20% in cases of pneumonia in patients older than 75 years.

In adults, IPD manifests as pneumonia in 50% to 80% of cases, and the morbidity and mortality of pneumonia in adults are considerable. Incidence increases from the fifth decade onward, and mortality is 1% to 2% in outpatients, rising to 10% to 20% in hospitalized patients. Approaching 50%, mortality is highest among patients admitted to the ICU.

Depending on the country, S. pneumoniae is estimated to cause up to 68% of cases of CAP, the burden of which is especially high in adults. Approximately 20% to 25% of adults with CAP are hospitalized, Prof. Welte told delegates, and mortality among hospitalized patients increases with age. In those aged 50 to 59 years, for example, the mortality rate reaches almost 7% and exceeds 25% in those patients 90 years and older. In nursing homes, S. pneumoniae is far and away the predominant pathogen responsible for CAP. Fewer than 30 S. pneumoniae serotypes account for more than 90% of adult fatalities related to IPD. In adults older than 16 years, serotypes 19A and 3 are associated with case fatality rates of about 50%. “Some serotypes are not covered by vaccines, and these have the highest mortality,” noted Prof. Welte.

Influence of Comorbidities

Comorbidities increase the risk and severity of adult pneumococcal disease, confirmed Prof. Welte. Nonpulmonary malignancies have the greatest impact on both CAP and IPD, although renal and cardiac diseases and other pulmonary conditions are important. Hospitalized patients with comorbidities have a mortality rate of 17.4%, according to 2005-2006 data from Germany. An observational study conducted at the Veterans Affairs Hospital in Louisville, Kentucky, revealed an association between CAP and acute myocardial infarction, which occurred in 20% of CAP patients who developed respiratory failure or shock. Thirty-day and 90-day mortality are significantly higher in patients with CAP who have chronic obstructive pulmonary disease (COPD) compared to those without COPD. Patients with COPD have a higher pneumonia severity index and a higher rate of admittance to the ICU.

CAP Diagnosis Is Challenging

CAP must be distinguished from nonpneumonic lower respiratory infections, which can be challenging, stated Dr. Mary Slack, Health Protection Agency Microbiology Services Division, Colindale, London, UK. According to Dr. Slack, although the gold standard is chest X-ray and identification of the respiratory pathogen, “this is rarely done in practice.” Traditional laboratory tests (i.e. blood and sputum culture) are of limited value, Dr. Slack told delegates. Pneumococcus accounts for at least 35% of CAP, but no pathogen is isolated in about 50% of cases of CAP, and pneumococcus probably causes a considerable proportion of CAP in the cases in which no pathogen is identified, she added.

Trends in Adult IPD Serotypes in Canada

Serotyping of respiratory tract isolates by the Toronto Invasive Bacterial Disease Network reveals that since the introduction of routine pediatric pneumococcal conjugate vaccine (PCV)7, the incidence of adult IPD in Toronto due to PCV7 serotypes has decreased while that of PCV13 and non-PCV isolates has increased. (Routine pediatric PCV7 was introduced in Canadian provinces between 2002 and 2005.) From 2002-2009, the proportion of IPD due to PCV7 serotypes decreased from 57% to 17% while the proportion of isolates from serotypes not in PCV7 but in PCV13 increased from 17% to 44%. Non-PCV serotype disease has increased from 1.2 to 2.0/100,000/year in adults younger than 65 years and from 9.7 to 12/100,000/year in those 65 and older.

Prevention Rather than Treatment Is the Key

Reducing the mortality associated with CAP and IPD will require stronger preventive measures, stressed Dr. Welte. Pediatric vaccination with the PCV7 vaccine has had a profound effect on macrolide resistance. Findings from bacterial isolates submitted to the Canadian Bacterial Surveillance Network indicate that IPD due to PCV7 serotypes in adults have decreased since the introduction of PCV7 programs in children. From 2000-2009, the per cent of IPD due to serotypes in PCV7 decreased from 56% to 18%, while the per cent of serotypes not in PCV7, but in PCV13 increased from 18% to 43%. From 2000-2009, resistance to at least 1 antibiotic class increased from 16% to 27%, and multidrug resistance increased from 1% to 5%.

Vaccination in previously unvaccinated adults may offer long-term protection. Conjugate vaccines may have an advantage in protecting against invasive disease due to the conjugation of a plain polysaccharide to a carrier protein, noted Prof. Behazine Combadière, INSERM, Paris, France. The conjugation “allows a T-dependent immune response to the polysaccharide antigen, which has the advantage of generating higher-affinity antibodies, immunological memory and responsiveness to booster doses of vaccine,” she explained to delegates.

Two new studies demonstrate that the 13-valent PCV (PCV13) is at least as immunogenic as a nonconjugated pneumococcal polysaccharide vaccine for the 12 serotypes common to both vaccines. These findings were demonstrated in adults at least 50 years old who were either unvaccinated previously or were previously immunized with the pneumococcal polysaccharide vaccine, reported Dr. Lisa A. Jackson, Group Health Research Institute, Seattle, Washington.

The two studies involved more than 2170 patients, 1 of which enrolled exclusively patients 70 years or older previously vaccinated with the polysaccharide vaccine at least 5 years earlier. The other study enrolled 835 vaccine-naïve adults aged 60 to 64 years who received either a single dose of PCV13 or the polysaccharide vaccine, and an additional group of 404 adults aged 50 to 59 years who received PCV13 in an open-label fashion.

Secondary end point data from these studies showed that 1 dose of PCV13 elicited a statistically significantly higher functional antibody response than the pneumococcal polysaccharide vaccine against most serotypes common to both vaccines and serotype 6A, a serotype included only in the PCV13. In both studies, the vaccines produced similar side effects, mostly local injection-site reactions.

Summary

Investigators here agreed that IPD and CAP in adults are very important worldwide concerns. Age is a primary risk factor for pneumococcal disease and the case-fatality rate of IPD increases with age. Comorbidities increase the risk and severity of adult pneumococcal disease. Diagnosis can be problematic even with the most rigorous investigation, complicating treatment. Therefore, a strategy of prevention through vaccination against the most serious IPD serotypes promises to provide substantial impact in reducing morbidity and mortality from IPD in the future. Vaccination with a conjugated vaccine can provide important efficacy against invasive disease and has been demonstrated to be at least as immunogenic as a nonconjugated polysaccharide vaccine in adults for the 12 serotypes common to both vaccines.