Epidemiology and outcome of invasive pneumococcal disease among adults in Belgium , 2009 – 2011

J Verhaegen (jan.verhaegen@uzleuven.be)1, J Flamaing2, W De Backer3, B Delaere4, K Van Herck5,6, F Surmont7, Y Van Laethem8, P Van Damme5, W Peetermans9 1. Department of Microbiology, University Hospitals Leuven, KU Leuven, Belgium 2. Department of Geriatric Medicine, University Hospitals Leuven, KU Leuven, Belgium 3. Department of Respiratory Medicine, University Hospital Antwerp, Antwerp, Belgium 4. Infectious Diseases Department, Cliniques Universitaires UCL de MontGodinne, Yvoir, Belgium 5. Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium 6. Department of Public Health, Ghent University, Ghent, Belgium 7. Medical Department, Specialty Care Business Unit Pfizer, Brussels, Belgium 8. Department of Infectious Diseases, St Pierre Hospital, Brussels, Belgium 9. Department of Internal Medicine and Infectious Diseases, University Hospitals Leuven, KU Leuven, Belgium


Introduction
In industrialised countries, the risk of invasive pneumococcal disease (IPD) remains high among older adults despite the availability of the 23-valent pneumococcal polysaccharide vaccine (PPV23) since 1983 [1].In a large number of these countries, including Belgium, PPV23 is recommended since 1985 for all adults ≥65 years of age and for persons between two and 64 years-old at high risk for pneumococcal infections due to living conditions or underlying medical conditions including asplenia, human immunodeficiency virus (HIV) infection, immunodeficiency or chronic cardiac, pulmonary, renal or hepatic diseases as from 50 years of age [2,3].In 2004, the 7-valent pneumococcal conjugate vaccine (PCV7) for infant vaccination became available in Belgium in a 3+1 schedule at full charge of the parents and, in 2007, PCV7 was added free of charge to the universal infant vaccination programme in a 2+1 schedule at two, four and 12 months of age.Since September 2011, PCV7 has been replaced by the 13-valent pneumococcal conjugate vaccine (PCV13) in the Belgian childhood vaccination schedule.In 2011, PCV13 was also approved by the European Medicines Agency for the prevention of IPD in adults ≥50 years of age [4].The Belgian recommendations regarding pneumococcal vaccination in adults were updated in July 2013 to also include PCV13 [2], however, there is no publicly funded pneumococcal vaccination programme for adults in Belgium.
A national IPD surveillance programme has existed in Belgium since 1986.It monitors the number of cases for all ages, type of IPD, serotypes or serogroups, and antibiotic susceptibility, but only few clinical data [5].An active IPD surveillance network for young children started in Belgium in 2002 [6,7].It showed that, two years after implementation of PCV7 in children <2 years of age, the incidence of vaccine-serotype IPD declined by 96% in this population but that the incidence of non-vaccine-serotype IPD increased two to three-fold [6].Because the clinical data to assess the burden of disease in adults were lacking, a prospective, active, hospital-based study was started in 2009 to analyse the morbidity and case fatality rate of IPD in adults aged ≥18 and ≥50 years, the distribution of pneumococcal serotypes and their antibiotic susceptibility, and the factors affecting disease outcome.We report the results for three years (2009)(2010)(2011) of this study to document the epidemiology and the burden of IPD before the introduction of PCV13.

Study design
This is a prospective, active, hospital-based epidemiological study of IPD in adults in Belgium.Fifty hospitals participated, corresponding to 44% of the acute care hospitals in Belgium.Three of these hospitals provided data for only the first year of the study, five during two years, and 42 during the three-year study period.
Adults hospitalised with microbiologically confirmed IPD (defined as isolation of Streptococcus pneumoniae from a normally sterile body site such as blood or cerebrospinal fluid) were eligible for inclusion.During the first year of study (2009), only adults aged ≥50 years were included, but as of 2010, the study was extended to all adults aged ≥18 years.The patient or a legal representative gave an informed consent for inclusion.If no informed consent was obtained, the patient was considered as a screen failure and clinical data were excluded from the analysis.The study was approved by the institutional review boards and local ethics committees of the participating hospitals.General baseline information was collected at inclusion, including detailed demographics, type of IPD, laboratory data, relevant medical history, and previous vaccination against S. pneumoniae and seasonal influenza.The clinical presentation, complications, diagnostic procedures, and treatment were documented by the treating physician during hospital stay.The disease outcome and persisting symptoms and signs were documented at discharge and one month after discharge.All patients were managed according to the hospital's standard protocol for IPD.

Microbiology
Pneumococcal culture was carried out by the clinical microbiology laboratory of each hospital using routine techniques.Pneumococcal isolates inoculated on blood agar plates or tubes were sent to the Belgian National Reference Laboratory for Pneumococci (University of Leuven, Belgium) for capsular typing and antibiotic susceptibility testing.
For isolates with oxacillin zone diameters ≤19 mm, penicillin minimum inhibitory concentrations (MICs) were determined with Epsilometer (E)-test on Mueller Hinton blood agar plates.For the interpretation of penicillin MIC results, criteria for parenteral penicillin (non-meningitis) were used.

Statistical analysis
Calculations and statistical analyses were performed with SAS (version 9.3 for Windows) statistical package (SAS Institute, Cary, NC).Quantitative variables were expressed as means and standard deviations (SD) or as medians and interquartile ranges (IQR).Categorical findings were summarised in frequency tables.Mean values were compared by one way analysis of variance, whereas proportions were compared using the chi-squared or Fisher's exact test.The association between outcome at discharge and covariates (age, IPD type, comorbidities, and vaccination status) was assessed by univariate and multivariate ordinal logistic regression and was expressed as an odds ratio with a 95% confidence interval (95% CI).In general, 'age' was preferred to age categories.A two-tailed p-value <0.05 was considered statistically significant.

Participants
A total of 1,875 patients hospitalised with IPD were eligible.Informed consent was not obtained for 467 patients and, therefore, clinical data from these patients were excluded from analysis.In most cases, the informed consent was not obtained because of the patient's poor physical condition or because the patient was discharged before microbiological confirmation of IPD.Average age and sex ratio of these patients were similar to the analysed population (data not shown).
To avoid inclusion of nosocomial IPD cases, 76 IPD cases were also excluded because the interval between hospitalisation and blood draw was ≥5 days.Thus, 1,332 patients were included in the analysis, with only 220 of them being between 18 and 49 years of age partly because patients in this age group were only included during the last two years of the study.A total of 208 patients died during hospitalisation.Of the 1,124 patients who were discharged from hospital, 141 (13%) were lost to follow-up so that one-month followup results were analysed in 983 patients.
Of the total 1,332 patients included in the analysis 52% were male and the mean age was 66 years (range: 18-98).Three age groups comprising 18 to 49 yearolds, 50 to 64 year-olds and those aged ≥65 years were considered for the study, however in some analyses patients aged ≥50 years were compared to those aged 18 to 49 years.Baseline characteristics for the three age groups are described in Table 1.The number of cases increased with age and the majority were ≥65 yearsold.Comparing the number of cases per year per age group (110 in the 18-49 years, 121 in the 50-64 years and 237 in the ≥65 years) with the size of the population in Belgium per age group at the time of the study (4.6 million 18-49 year-olds, 2 million 50-64 year-olds and 1.8 million ≥65 year-olds), there appeared to be almost three times more cases in the 50 to 64 years age group compared to the 18 to 49 years, and almost six times more cases in the ≥65 year-olds.
Most patients had at least one chronic comorbidity, and the proportion increased from 54% (118/220) in patients aged between 18 and 49 years to 85% (627/742) in patients aged ≥65 years.Furthermore, 45% (603/1,326) of patients had ≥2 predisposing comorbidities.Chronic obstructive pulmonary disease and cancer were the most frequent comorbidities in the two older age groups.Even though the vast majority of patients had a comorbidity or were at an age where pneumococcal vaccination is recommended, less than 10% (92/1,332) were vaccinated with PPV23.Vaccination against seasonal influenza increased with increasing age, from 8% (18/220) in patients aged between 18 and 49 years to 44% (326/742) in patients aged ≥65 years.Nearly 5% (66/1,332) of patients took oral antibiotics within 24 hours before hospitalisation.

Type and outcome of invasive pneumococcal disease
Of the 1,332 patients, 1,049 (79%) had bacteraemic pneumonia (Table 2).Patients aged between 18 and 49 years were hospitalised for a median duration of 7.5 days (IQR: 5-13) compared to 12 days (IQR: 7-22) for patients aged ≥50 years.Admission to an intensive care unit (ICU) was more frequent in older patients (42% (154/370) in 50-64 year-olds vs. 25% (54/219) in 18-49 year-olds; p=0.001) and for patients with meningitis (81% (59/73); p=0.0001) (Table 3).Only 16% (12/73) of patients with bacteraemia without focus were admitted to ICU.Depending on the age group, the median durations of stay in an ICU varied from four to six days (IQR: 2-15), with four days for the 18 to 49 year-olds, six days for the 50 to 64 year-olds and five days for those aged ≥65 years, The median durations of hospitalisation after discharge from ICU were seven to 10.5 days (IQR: 0-21), with seven days for the 18 to 49 year-olds, nine days for the 50 to 64 year-olds and 10.5 for those 65 years-old and over.The median duration of ICU stay was significantly higher for deceased patients (9 vs. 5 days, p=0.0009).
For empirical treatment before the microbiological results became available, the three most used antibiotics on patients with available data (n=1,327) were amoxicillin-clavulanic acid intravenous (in 615 (46%) patients), third-generation cephalosporin (in 116 (9%) patients), and fluoroquinolones (in 71 (5%) patients).Also, 65 (5%) patients received a combination of amoxicillin-clavulanic acid and macrolides.After microbiological diagnosis, antibiotic treatment was changed to amoxicillin in 142 patients and penicillin in 151 patients.Overall, the antibiotic treatment was adapted in 55% (723/1,327) of patients after the microbiological results became available.The majority of the 73 patients with meningitis were treated with third-generation cephalosporin (51 patients) or penicillin (16 patients).

Discussion
In 2009, a prospective, active hospital-based study of morbidity and mortality of IPD in adults was started in Belgium.Data collected between 2009 and 2011 showed that mortality due to IPD was high, with up to 20% case fatality in adults ≥65 years of age.Bacteraemic pneumonia was the most frequent clinical type of IPD.Of the 1,214 serotyped isolates, 742 (61%) were included in PCV13, which thus included the most resistant and lethal isolates.
As in the current study, previous studies in the Netherlands, Spain and the United States (US) have shown that bacteraemic pneumonia predominates in adults [9][10][11].Meningitis has been reported to be more frequent in young children [11,12].In addition, we confirmed age as a risk factor for IPD and death due to IPD [11].Chronic illness is another well-known risk factor for IPD [13][14][15].In our study, more than threequarters of patients with IPD had at least one chronic underlying condition.This proportion was even higher for older adults.This confirms that patients with comorbidities have a higher risk of developing IPD.
Patients with at least one comorbidity generally also had a higher risk of death in hospital due to IPD.
Universal mass vaccination of children aged <2 years with PCV7 has dramatically decreased the incidence of vaccine-type IPD in this population and, to a lesser extent, in older individuals through herd effect [16][17][18].Nevertheless, even with successful mass vaccination, IPD remains a problem.The ongoing national surveillance will help determine how routine use of PCV13 in children further influences the epidemiology of IPD in adults.While PCV7-type IPD has decreased [17,18], non-PCV7-type IPD has risen in many countries [17,[19][20][21][22][23].Accordingly, we found 7% of IPD cases in adults caused by serotypes included in PCV7.Because four of the most frequent serotypes (7F, 1, 19A, and 3) in our study are included in the newly licensed PCV13, they should become less common as the use of PCV13 increases.
Our finding that serotypes 1, 7F, and 19A predominate corresponds with other reports [6,19,[23][24][25].Serotype 19A was the third most prevalent serotype in adult IPD.Similarly, this serotype was previously reported as the second or third most prevalent serotype in IPD in children <5 years of age [6,7].This is a concern because serotype 19A is frequently multi-resistant to antibiotics.The incidence of serotype 19A started to increase in children before the introduction of PCV7 and further increased after its introduction [6], suggesting that the rise is partly due to other factors, such as antibiotic consumption and secular trends.Serotypes 12F and 22F were the fifth and sixth most common serotype.
Serotype 12 F has also become more common in young children since 2002-2003 [6].Both serotypes are included in PPV23 but not in PCV13 and should be closely monitored in the future.
According to a review article, the reported case fatality rate for adult patients hospitalised with IPD has remained relatively stable at approximately 12% since the 1950s [26].We found a slightly higher rate of 16%.The case fatality rate was low for serotypes 1 and 5 and high for serotypes 3 and 6B, as shown in previous studies in Denmark, the Netherlands and the US, [16,27,28].
One limitation of our study is that older patients may have been over-represented because adults between 18 and 49 years of age were included only from the second year of study (2010), whereas adults≥50 years of age were included from the beginning of the study (2009).However, this should have little impact on the results because per year the majority (51%) of patients were ≥65 years of age, and the data were analysed per age group.Another possible bias of the results is that 543 of the 1,875 (28%) eligible patients were not included in the analysis due to unavailable informed consent or late blood draw.Disease in these patients may have been more severe (patients in ICU) or less severe (patients who left the hospital before microbiological confirmation of IPD) than in the analysed population.
In conclusion, this study showed that, in Belgium, the mortality of IPD in adults is high, with a case fatality rate of 20% in patients ≥65 years of age.The most common and virulent pneumococcal serotypes are included in PCV13, which adds support for the use of this vaccine in combination with the PPV23 in high-risk and older adults.In addition, these data are essential when assessing the impact of PCV13 vaccination in adults in the future.

Table 1
Baseline characteristics of patients with invasive pneumococcal disease by age group,Belgium, 2009Belgium,  -2011 (n=1,332)    (n=1,332) a Only comorbidities found in more than 10% of the patients are shown.

Table 2
Distribution of invasive pneumococcal disease types by patient age,Belgium, 2009Belgium,  -2011 (n=1,332)    (n=1,332) a Streptococcus pneumoniae isolated from blood culture without localised infection identified.

Table 3
Admission to intensive care unit and disease outcome at discharge by age and type of invasive pneumococcal disease, Belgium, 2009-2011 (n=1,329) a CI: confidence interval; ICU: intensive care unit; OLR: ordinal logistic regression; SD: standard deviation.a Data missing for three patients.

Table 4
Disease outcome at discharge for patients with invasive pneumococcal disease, by comorbidity, Belgium, 2009-2011 (n=1,329) a CI: confidence interval; COPD: chronic obstructive pulmonary disease; HIV: human immunodeficiency virus; IPD: invasive pneumococcal disease; OLR: ordinal logistic regression; SD: standard deviation.a Data missing for three patients.