Invasive Pneumococcal Disease Mortality Research Articles

Mortality of Invasive Pneumococcal Disease following Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in Greenland.

Before the incorporation of the 13-valent pneumococcal conjugate vaccine (PCV13) into the childhood vaccination regimen in Greenland in 2010, Inuit populations experienced a substantial prevalence of invasive pneumococcal disease (IPD). The PCV13 introduction has been shown to markedly reduce the incidence of IPD. This current study estimated the impact of PCV13 introduction on IPD mortality in Greenland. This was a nationwide register-based study using all available data on IPD cases 1995-2020 in Greenland. Thirty-one-day IPD case fatality rates (CFR), and all-cause and mortality rates associated with IPD during the period before the introduction of PCV13 (January 1995 to September 2010) were compared with those observed in the post-PCV13 era (September 2010 to October 2020). Standardized mortality ratios (SMRs) expressed differences in mortality by sex, age, region, ethnicity, comorbidity, and serotype. IPD CFR decreased with 24.5% from the pre- to the post-PCV13 period. SMR in IPD patients decreased by 57% (95% CI, 36-75%), and a reduction occurred in all age groups. While SMR in IPD persons ≥60 years remained virtually unchanged, there were no IPD-related deaths in persons ≤39 years in the post-PCV13 period. In conclusion, IPD-related mortality has decreased in Greenland following PCV13 introduction in 2010 in the country.

Cost-effectiveness of the 20-valent pneumococcal conjugate vaccine versus the 23-valent pneumococcal polysaccharide vaccine for older adults in South Korea

BackgroundDespite the demonstrated immunogenicity and safety of the 20-valent pneumococcal conjugate vaccine (PCV20) in older adults, the cost-effectiveness of the PCV20 was not examined compared to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in South Korea. Therefore, this study aimed to evaluate the cost-effectiveness of PCV20 compared with PPSV23 in adults aged 65 years and older in South Korea. MethodsWe constructed a Markov model that included susceptible states, invasive pneumococcal disease (IPD), non-bacteremic pneumonia (NBP), and death. The population was categorized by disease risk status (low risk, moderate risk, and high risk) and age group (65–74/75–84/85–99 years) at model entry. The annual incidence and mortality of IPD and NBP associated with PCV20 and PPSV23 were estimated based on serotype coverage, vaccine coverage, and vaccine effectiveness. The disease costs and utilities were obtained from previous studies. The incremental cost-effectiveness ratio (ICER) was used to evaluate cost-effectiveness within the threshold of 16,824 USD per quality-adjusted life-year (QALY). ResultsAmong the total population (n = 8,843,072), PCV20 prevented 1941 and 50,575 cases of IPDs and NBPs, respectively, and 898 and 8593 deaths due to IPDs and NBPs compared to PPSV23. The total medical cost per person was 12.11 USD higher in PCV20, with a gain of 0.0053 LYs and 0.0045 QALYs per person. The ICER for PCV20 and PPSV23 was 2270 USD/LY and 2677 USD/QALY. ConclusionsIn South Korea, PCV20 is a cost-effective option compared with PPSV23 for adults aged 65 years and older. These cost-effectiveness results provide evidence for decision-making regarding the approval and National Immunization Program implementation of PCV20.

Nasopharyngeal Carriage and Serotype Distribution of Streptococcus pneumoniae in Elderly: A Cross-sectional Study in Turkey.

The incidence and mortality of invasive pneumococcal disease are much higher in people over 65 years compared to the general population. The incidence of the disease and the distribution of serotypes changed with the spread of childhood conjugate pneumococcal vaccines and the use of vaccines in the adult age group. Nasopharyngeal carriage is an important stage in the disease pathogenesis. In this study, we aimed to determine the pneumococcal carriage prevalence and serotype distribution in adults aged ≥ 65 years living in a nursing home. The nasopharyngeal swabs were taken from ≥ 65 years old people living in Narlıdere Nursing Home. The specimens were cultured and pneumococci were isolated according to colony appearance, optochin sensitivity and solubility in bile salts. Pneumococcal serotypes were identified using the capsule swelling reaction. Pneumococcus was isolated in 10 of 341 subjects and the pneumococcal carriage prevalence was 2.9%. Advanced age, immunocompromised status and chronic renal failure were associated with pneumococcal carriage. In multivariate model, having immunocompromised status was significantly associated with carriage. Serotypes/serogroups of pneumococci were 7F, 23F, 10, 11, 15. 17, 20 and 33. The 13 valent conjugated pneumococcal vaccine serotype carriage prevalence was 0.6%. Although pneumococcal colonization in older people is uncommon, most of the isolated serotypes are not PCV13 serotypes. The monitoring of pneumococcal serotypes can offer useful information about the circulation of this pathogen among older people and the potential protective effect of pneumococcal vaccines.

Clinical characteristics, antimicrobial resistance, and risk factors for mortality in paediatric invasive pneumococcal disease in Beijing, 2012\u20132017

BackgroundTo analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing.MethodsPaediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed.ResultsOverall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count < 4000 cells/μL were independent risk factors for mortality.ConclusionMeningitis was the most common clinical manifestation of IPD, and was frequently associated with death. Strains in the PCV13 vaccine would cover most of the cases, and so wider use of PCV13 should be considered.

Incidence and Mortality Trends of Acute Gastroenteritis and Pneumococcal Disease in Children Following Universal Rotavirus and Pneumococcal Conjugate Vaccination in Ecuador.

IntroductionEcuador introduced routine infant rotavirus (RV) vaccination in 2008 and pneumococcal conjugate vaccination (PCV) in 2011 to manage disease and mortality in children caused by gastroenteritis (GE) and by pneumonia (PNE) and invasive pneumococcal disease (IPD), respectively.MethodsThis retrospective ecological database study described vaccination coverage as well as the trends in incidence and mortality in the pre- versus post-vaccination periods and used time-trend analysis models to assess the impact of vaccination.ResultsRV vaccination coverage of the second dose was between 79–97% from 2008 to 2016. GE incidence and mortality showed a declining trend before vaccination which continued in the post-vaccination period. The model estimated a statistically significant decrease of 72.4% for GE mortality and 51.2% for GE incidence in the post-vaccination period. PCV vaccination coverage remained above 80% (second dose) and 40% (third dose) after 2011. PNE mortality showed a declining trend before vaccination and a continued decline after vaccination, while PNE incidence was more variable (sharp increase from 2005–2009 then decrease and eventual stabilisation). The model estimated a statistically significant decline of 41.1% for PNE mortality and a stable PNE incidence in the post- versus pre-vaccination period. IPD incidence and mortality yearly data showed large variability by year and low numbers, making it difficult to discern a trend. The model estimated a statistically significant reduction of 51.1% for IPD mortality and 31.5% for IPD incidence in the post- versus pre-vaccination period.ConclusionAfter the first 9 years of routine RV vaccination and 6 years of routine PCV vaccination in Ecuador, significant decreases in incidence and mortality in children < 5 years of age due to GE and pneumococcal disease have been observed.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00531-6.

Relationship between serotypes, disease characteristics and 30-day mortality in adults with invasive pneumococcal disease.

Invasive pneumococcal disease (IPD) is responsible for substantial mortality and morbidity worldwide. We aimed to identify host and bacterial factors associated with 30-day mortality in 18-year-old patients hospitalized with IPD in France from 2013 to 2015. This study analyzed data collected from consecutives IPD cases included in two parallel multi-center cohort studies: COMBAT study (280 patients with pneumococcal community-acquired bacterial meningitis) and SIIP study (491 patients with non-meningitis IPD). Factors associated with 30-day mortality were identified using logistic regression. Among the 771 enrolled patients (median age 66years, IQR [52.0-79.7]), 592/767 (77.2%) had at least one chronic disease. Patients with meningitis were younger (60.2 vs 70.9years; p < 0.001) and had fewer chronic diseases than those with non-meningitis IPD (73.3% vs 79.4%; p = 0.05). Non-vaccine serotypes were more frequent in meningitis patients than in those with other IPD (36.1% vs 23.1%; p < 0.001). The overall 30-day mortality was 16.7% and patients with concurrent meningitis and extra-cerebral IPD had the highest 30-day mortality rate (26.5%). On multivariate analyses, older age, history of malignant solid tumor, meningeal IPD and serotypes previously identified with high mortality potential were independently associated with 30-day mortality. Of the serotypes with high mortality potential, 80% were included in licensed (PCV13 or PPV23) vaccines. We observed an effect of both host factors and pneumococcal serotypes on 30-day mortality in IPD. This highlights the need for a focused strategy to vaccinate at-risk patients. ClinicalTrial. Gov identification number: NCT01730690.

Prognostic factors for mortality in invasive pneumococcal disease in adult: a system review and meta-analysis

Risk factors associated with mortality in invasive pneumococcal disease remain unclear. The present work is a meta-analysis of studies that enrolled only patients with invasive pneumococcal disease and reported on mortality. Potentially eligible reports were identified from PubMed, CHAHL, and Web of Science, comprising 26 reports in total. Overall mortality for invasive pneumococcal disease was reported as 20.8% (95% confidence interval (CI) 17.5–24%). Factors associated with mortality were age (odds ratio (OR) 3.04, 95% CI 2.5–3.68), nursing home (OR 1.62, 95% CI 1.13–2.32), nosocomial infection (OR 2.10, 95% CI 1.52–2.89), septic shock (OR 13.35, 95% CI 4.54–39.31), underlying chronic diseases (OR 2.34, 95% CI 1.78–3.09), solid organ tumor (OR 5.34, 95% CI 2.07–13.74), immunosuppressed status (OR 1.67, 95% CI 1.31–2.14), and alcohol abuse (OR 3.14, 95% CI 2.13–4.64). Mortality rates with invasive pneumococcal disease remained high, and these findings may help clinicians provide appropriate initial treatment for this disease.

Analysis of serotype and clinical manifestation of 80 children with invasive pneumococcal disease in Suzhou

Objective To understand serotypes and clinical manifestation of children with invasive pneumococcal disease (IPD) in Suzhou, so as to find a better strategy for reducing the incidence and mortality of IPD. Methods Eighty children with IPD were enrolled into our study from January 2011 to December 2015.The data of epidemiology, serotype, clinical manifestation, laboratory results and prognosis were collected and analyzed. Results The mortality of 80 children with IPD was 17.5%(14/80). Sixty percent of them were younger than 2 years old, and 78.6% of 14 dead cases were younger than 2 years old, the median age of dead group 0.68 (0.45, 2.07) years was younger than 1.61 (0.85, 3.45) years of survival group (P 0.05). The drug resistance rates of 80 pneumococcus to Erythromycin, Clindamycin, Tetracycline, Sulfamethoxazole, Penicillin, Cefotaxime, Amoxicillin, Chloramphenicol, Vancomycin and Levofloxacin were 100% (80/80), 98.8% (79/80), 88.8%(71/80), 71.3%(57/80), 48.8%(39/80), 32.5%(26/80), 8.8%(7/80), 5.0%(4/80), 0(0/80) and 0(0/80) respectively.Eight serotypes of 80 IPD cases were listed in descending order: 6B(25.5%, 20/80), 14(23.8%, 19/80), 19F(15.0%, 12/80), 19A(15.0%, 12/80), 23F(8.8%, 7/80), 20(5.0%, 4/80), 9V(5.0%, 4/80) and 15B/C(2.5%, 2/80), and 6 serotypes of 14 dead cases were: 6B(35.7%, 5/14), 14(28.6%, 4/14), 19F(14.3%, 2/14), 19A(7.1%, 1/14), 23F(7.1%, 1/14) and 20(7.1%, 1/14); the coverage of IPD serotypes of 7-valent pneumococcal conjugate vaccine (PCV7) 77.5%(62/80) was lower than 92.5%(74/80) of 13-valent pneumococcal conjugate vaccine (P<0.05). Conclusion Majority of dead cases of IPD is always younger than 2 years.The low coincidence rate of choices of antibiotics to invasive pneumococcus outpatient and low rate of PCV immunization in China are responsible for the high mortality of IPD.Timely recognition of continuous hyperpyrexia, vomiting and somnolence in early stage and appropriate use of antibiotics is the key to improve the outcome of IPD.Thirteen-valent pneumococcal conjugate vaccine immunization provides a robust strategy for reducing the incidence and mortality of IPD. Key words: Pneumococcus; Serotype; Invasive disease; Dead; Drug resistance,

Adult invasive pneumococcal disease in the Republic of Korea: Risk medical conditions and mortality stratified by age group

ObjectivesThis study aimed to characterize the risk factors for mortality in adult patients with invasive pneumococcal disease (IPD) stratified by age groups, after implementation of the national immunization program of 23-valent polysaccharide vaccine (PPSV23) for those aged ≥65 years in the Republic of Korea (ROK). MethodsClinical data and pneumococcal isolates from adult patients with IPD (≥18 years of age) were collected prospectively from 20 hospitals through the nationwide surveillance program from March 2013 to October 2015. ResultsA total of 319 patients with IPD were enrolled. Median age was 69 years. Overall in-hospital mortality was 34.2%: 17.1% in those aged 18–49 years, 23.7% in those aged 50–64 years, 33.0% in those aged 65–74 years, and 51.0% in those aged ≥75 years (p<0.001). In particular, early death within 7days of hospitalization accounted for 60.6% (66/109). While old age (≥65 years), higher Pitt bacteremia score (≥4), and bacteremic pneumonia were independently associated with IPD mortality in all age groups, an additional mortality risk factor of immunocompromised status was identified for patients aged 50–64 years. PPSV23 serotypes accounted for 64.4% (122/189) of the pneumococcal isolates serotyped. ConclusionsThis study suggests that vaccine-type IPD continues to place a substantial burden on older adults in the ROK, necessitating an effective vaccination strategy for those at higher risk.

Should UK Pneumococcal Vaccine Eligibility Criteria Include Alcohol Dependency in Areas with High Alcohol-Related Mortality?

A recently reported steep increase in the incidence of invasive pneumococcal disease (IPD) in adults in the North East of England was primarily associated with pneumococcal sero-types found in the 23-valent pneumococcal polysaccharide vaccine (PPSV23). This region also has one of the highest rates of alcohol-related premature mortality and morbidity in the UK. Given that alcohol dependence is long acknowledged as one of the strongest risk factors for IPD mortality, we feel there is an increasingly compelling case to look again at the divergence of UK vaccine guidance from that of the World Health Organisation and the Centre for Disease Control in the USA, in the non-inclusion of alcoholism as an indicator condition that would potentially benefit from receiving PPSV23 vaccine. Such a re-think would represent a responsible evaluation of vaccination guidance in the face of newly emerging epidemiological findings and would have the potential to save lives in a very marginalised and vulnerable section of the population. We propose therefore that alcohol dependency (now referred to as alcohol use disorder), should be re-considered an indicator condition for receiving pneumococcal vaccine in North East England, where mortality from pneumococcal disease has been rising and which already has an excessive burden of alcohol-related mortality.

Phage-Derived Protein Induces Increased Platelet Activation and Is Associated with Mortality in Patients with Invasive Pneumococcal Disease.

ABSTRACTTo improve our understanding about the severity of invasive pneumococcal disease (IPD), we investigated the association between the genotype of Streptococcus pneumoniae and disease outcomes for 349 bacteremic patients. A pneumococcal genome-wide association study (GWAS) demonstrated a strong correlation between 30-day mortality and the presence of the phage-derived gene pblB, encoding a platelet-binding protein whose effects on platelet activation were previously unknown. Platelets are increasingly recognized as key players of the innate immune system, and in sepsis, excessive platelet activation contributes to microvascular obstruction, tissue hypoperfusion, and finally multiorgan failure, leading to mortality. Our in vitro studies revealed that pblB expression was induced by fluoroquinolones but not by the beta-lactam antibiotic penicillin G. Subsequently, we determined pblB induction and platelet activation by incubating whole blood with the wild type or a pblB knockout mutant in the presence or absence of antibiotics commonly administered to our patient cohort. pblB-dependent enhancement of platelet activation, as measured by increased expression of the α-granule protein P-selectin, the binding of fibrinogen to the activated αIIbβ3 receptor, and the formation of platelet-monocyte complex occurred irrespective of antibiotic exposure. In conclusion, the presence of pblB on the pneumococcal chromosome potentially leads to increased mortality in patients with an invasive S. pneumoniae infection, which may be explained by enhanced platelet activation. This study highlights the clinical utility of a bacterial GWAS, followed by functional characterization, to identify bacterial factors involved in disease severity.

Declining mortality from adult pneumococcal infections linked to children's vaccination

To determine changes in mortality among adults with invasive pneumococcal disease (IPD) after introducing pneumococcal conjugate vaccines (PCVs) in children. An active surveillance of adults with culture-proven IPD in Barcelona. Serotype-specific mortality and rates of disease and death were analysed in three periods: baseline (1994-2001), PCV7 (2002-2009) and PCV13 (2010-2013). Overall, IPD caused by PCV7 serotypes was associated with increased case fatality rate (24 percent). In patients 18-64 years (baseline vs. PCV7 vs. PCV13 periods), case fatality rate from IPD decreased (22 vs.14 vs. 12 percent), and it was associated with a decline in PCV7 serotypes (3.56 vs. 2.80 vs. 1.49 cases/10(5) person-years) and in PCV7 serotypes-specific death (0.74 vs. 0.53 vs. 0.09 deaths/10(5) person-years). In patients ≥65 years, case fatality rate did not change (24 vs. 22 vs. 24 percent); however, there was a decline in PCV7 serotypes-specific death (4.94 vs. 3.58 vs. 2.45 deaths/10(5) person-years), and an increase in non-PCV serotypes-specific death (2.55 vs. 3.70 vs. 4.09 deaths/10(5) person-years). The use of PCVs for children was associated with a reduction of mortality from IPD in adults 18-64 years, through the indirect effect of herd protection. In older adults, age-related factors could play a role in IPD mortality.

Global Pneumococcal Disease and Policies for Control

Global Pneumococcal Disease and Policies for Control

The Spectrum of Invasive Pneumococcal Disease in Adults in the XXI Century

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and bacterial meningitis in adults. Despite the availability of potent antibiotics and the development of different pneumococcal vaccines, the burden of pneumococcal infections in terms of morbidity, hospitalizations, mortality, and healthcare costs continues to be tremendous. The different pneumococcal serotypes play an important role in some aspects of pneumococcal epidemiology. The introduction of the 7-valent conjugate vaccine among children led to important changes not only in the epidemiology but also in the clinical outcomes and mortality of invasive pneumococcal disease in adults. Moreover, with the widespread use of immunosuppressive and immunomodulating therapies for different medical conditions, we may expect an increase in the number of patients at a high risk of pneumococcal infections in the following years. The influence of immunosuppression as a risk factor for invasive pneumococcal disease, the changes in the dynamics of pneumococcal serotypes, the influence of pneumococcal serotypes on the clinical presentation of pneumococcal invasive disease, and the role of pneumococcal vaccines are some of the important issues that are discussed in this review.

Role of an Iron-Dependent Transcriptional Regulator in the Pathogenesis and Host Response to Infection with Streptococcus pneumoniae

Iron is a critical cofactor for many enzymes and is known to regulate gene expression in many bacterial pathogens. Streptococcus pneumoniae normally inhabits the upper respiratory mucosa but can also invade and replicate in lungs and blood. These anatomic sites vary considerably in both the quantity and form of available iron. The genome of serotype 4 pneumococcal strain TIGR4 encodes a putative iron-dependent transcriptional regulator (IDTR). A mutant deleted at idtr (Δidtr) exhibited growth kinetics similar to parent strain TIGR4 in vitro and in mouse blood for up to 48 hours following infection. However, Δidtr was significantly attenuated in a murine model of sepsis. IDTR down-regulates the expression of ten characterized and putative virulence genes in nasopharyngeal colonization and pneumonia. The host cytokine response was significantly suppressed in sepsis with Δidtr. Since an exaggerated inflammatory response is associated with a poor prognosis in sepsis, the decreased inflammatory response could explain the increased survival with Δidtr. Our results suggest that IDTR, which is dispensable for pneumococcal growth in vitro, is associated with regulation of pneumococcal virulence in specific host environments. Additionally, IDTR ultimately modulates the host cytokine response and systemic inflammation that contributes to morbidity and mortality of invasive pneumococcal disease.

Effect of Serotype on Focus and Mortality of Invasive Pneumococcal Disease: Coverage of Different Vaccines and Insight into Non-Vaccine Serotypes

BackgroundDifferences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13).MethodSerotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients’ diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5–64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines.ResultsThe linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines’ coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals.ConclusionMarked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss.

How can we reduce the mortality of invasive pneumococcal disease?

In this issue of the European Respiratory Review , Ludwig et al . [1] present an article highlighting the continuous burden caused by invasive pneumococcal disease (IPD). Demographic changes due to the growing elderly population will further increase this problem. Bacterial infections of the upper and lower airways are most frequently caused by pneumococci in both adults and children, and pneumococci are an important cause of bacterial meningitis. Pneumococci carry a large armamentarium of pathogenesis factors enabling their translocation into the blood stream, i.e. bacteraemia, and which determine the amount of local tissue damage [2, 3]. These polygenic virulence capacities are the major cause of the high mortality of IPD. The mortality has not changed significantly in the past decades [4]. In addition to high mortality and morbidity, the IPD-induced healthcare costs are vast. New antibiotics might not have a great effect. In some countries, the resistance of pneumococci …

Factors Predicting Mortality in Invasive Pneumococcal Disease in Adults in Alberta

To define the factors associated with 30-day mortality among adult patients with invasive pneumococcal disease (IPD), we conducted a retrospective review of all cases of IPD in Alberta from 2000 to 2004. We hypothesized that multiple factors would be predictive of such mortality. We also examined the factors predictive of early (within 5 days of admission) mortality. We identified 1154 patients who met our inclusion criteria, 163 (14.1%) of whom died within 30 days. Over half (62.6%) of the deaths occurred within 5 days of admission. Ten factors were independently associated with increased 30-day mortality: 3 comorbidity factors-cancer within 5 years of diagnosis of IPD, diabetes, and cirrhosis; 4 complications-requirement for supplemental oxygen, mechanical ventilation, alteration of mental status, and cardiac arrest; 2 microorganism-related factors-infection with high- or infection with intermediate-mortality serotypes; and 1 treatment-related factor-treatment with a single antibiotic. Age 18-40 years and treatment with 2 antibiotics concurrently were associated with lower 30-day mortality. Comorbid illnesses were not contributory to early mortality (within 5 days of admission); instead, complications (alteration of mental status, requirement for supplemental oxygen, mechanical ventilation, and cardiac arrest) as well as infection with high-mortality serotypes and treatment with a single antibiotic were important. Age 18-40 years, infection with serotypes in the polysaccharide vaccine, and treatment with 2 or more than 2 antibiotics were associated with decreased early mortality. Early mortality accounted for 62.6% of the deaths. In conclusion, we found that mortality in IPD is multifactorial, the factors differ for 5- and 30-day mortality, and mortality is associated with host (age and complications), microorganism (pneumococcal serotypes), and therapeutic factors. Our data indicate that treatment with 2 or more antibiotics effective against Streptococcus pneumoniae should be used to treat IPD.

Serotype-Related Variation in Susceptibility to Complement Deposition and Opsonophagocytosis among Clinical Isolates of Streptococcus pneumoniae

The polysaccharide capsule is a major virulence factor of Streptococcus pneumoniae; it affects complement resistance and shields the bacterium from phagocytes. Certain capsular serotypes appear to be better able to cause invasive disease than others. Serotypes 1 and 5 are common causes of invasive disease but are rarely isolated from healthy carriers, whereas serotypes 6B and 23F are more frequently isolated from carriage than invasive disease. We have recently shown that serotypes 6B and 19F differ in resistance to complement C3 deposition and opsonophagocytic killing. In this study we assessed the complement resistance and susceptibility to opsonophagocytosis of several other serotypes targeted by the pneumococcal conjugate vaccines. Clinical isolates of serotypes 1, 4, 5, 14, 18C, and 23F were tested along reference strains of corresponding capsular types. The concentration of anticapsular antibodies required for opsonophagocytic killing correlated inversely with C3 deposition on the serotype. Serotype 1 was the most resistant of the clinical isolates to C3 deposition and, along with serotypes 5 and 19F, required the highest concentration of capsule antibodies for opsonophagocytic killing, whereas serotype 23F was the most sensitive to opsonophagocytosis. Sensitivity to C3 deposition and opsonophagocytosis was associated with serotype-specific mortality of invasive pneumococcal disease, suggesting that the primary pathogens, such as serotypes 1 and 5, are more resistant to complement and require a higher concentration of capsule antibodies for opsonophagocytic killing than the opportunistic serotypes such as 6B and 23F, which are associated with a more severe disease outcome.

Inhibition of T Cells Provides Protection against Early Invasive Pneumococcal Disease

Infections caused by Streptococcus pneumoniae are major causes of morbidity and mortality, which are in part mediated by immune cell-dependent mechanisms. Yet, the specific contributions of individual cell types to immunopathology are only partially understood. T cells are well characterized with respect to their function in protective humoral immune responses; however, their roles during early stages of infection and invasive pneumococcal disease (IPD) are less well defined. Using a mouse model of pneumococcal sepsis, we found that CD4(+) T cells were recruited to the lung as early as 12 h after intranasal infection. Recruitment was accompanied by upregulation of CD69 and B7-H1, reflecting T-cell activation. Unexpectedly, major histocompatibility complex (MHC) class II-deficient mice, which lack CD4(+) T cells, displayed an increased survival despite comparable bacterial titers in the blood, spleen, and lung. The higher survival correlated with a lower cytokine and chemokine response upon S. pneumoniae challenge in MHC class II-deficient mice, suggesting that inflammation may contribute to the mortality of IPD. Comparable to the case for MHC class II-deficient mice, antibody-mediated depletion of CD4(+) T cells and drug-induced inhibition of T-cell function with cyclosporine, or interference with T-cell activation using CTLA4-immunoglobulin (Abatacept), led to significant increases in survival during IPD. Our results reveal an important and adverse role of CD4(+) T cells in the pathogenesis of IPD and suggest that modulation of T-cell activation during early phases of S. pneumoniae invasive infection may provide a therapeutic option.