Among our cases comprising hospitalised patients with pneumococcal disease, majority were aged ≥65 years and of male gender, and about a quarter had a Charlson’s score of >3. The ethnic distribution of the patients was reflective of the national census 22. However, compared to the control group, IPD patients demonstrated a trend towards being younger, and with lower Charlson’s scores. Non-IPD patients were more similar to the control group, but with only slightly lower mean age and Charlson’s scores. In our study, patients in older age groups or with more co-morbidities might have had increased prior healthcare exposures, or had specific risk factors (such as swallowing impairment) which resulted in them being more likely to develop infections23,24 from other aetiologies other than S. pneumoniae 25,26. However, in contrast to the age and co-morbidity trends, the ICU admission and in-hospital mortality rates were highest in IPD patients and lowest in the control group. This reflects the virulence of the disease and highlights the importance of early recognition, treatment, and prevention where possible.
Our findings showed that prior pneumococcal vaccination was associated with a reduced risk of IPD by about 80% in our study population, after adjustments for age, gender, Charlson’s score and influenza vaccination status. This was consistent with studies in other settings evaluating the effectiveness of PCV13 and PPSV23 13-15. Pneumococcal serotypes covered by these vaccines have been shown to be well matched to those circulating in the Singapore population 6,10,27. In particular, serotypes 3, 6B, 7F, 8, 19A and 23F are predominant in the 19-64yrs age group, while serotypes 3, 14 and 19A are predominant among those 65yrs and above 27.
In addition, 50 (54.4%) of the IPD cases among our hospital patients were below 65yrs of age, of whom 24 (48.0%) had some form of chronic disease. A Japanese study of 10.4 million individuals demonstrated that younger adults with at least one medical condition were at greater risk of IPD compared to healthy older adults. For example, an adult aged 50-64yrs with an underlying medical condition had a higher risk compared to a healthy adult aged ≥65yrs 28. Although the overall incidence in younger adults is lower than in older age groups 4,29, the increased susceptibility of adults <65yrs with chronic diseases suggests that targeted efforts to vaccinate this population might be beneficial in reducing IPD incidence.
Currently, our hospital has ongoing vaccination programmes to identify and opportunistically vaccinate high-risk groups according to standardised protocols. In the inpatient setting, high-risk inpatients are counselled on and given vaccination prior to discharge, while in the outpatient setting, selected specialist clinics have a nurse-led programme for counselling and vaccination administration for high-risk patients, in conjunction with the medical consultation. Vaccination should also be provided by primary care practitioners as part of chronic disease management and alongside other preventive services such as health screening.
Our study, however, did not demonstrate any significant effect of PCV13 vaccination on reducing risk of pneumococcal disease, likely due to the low proportion of patients in our study with a clearly documented history of PCV13 vaccination. Apart from adult vaccination, widespread introduction of pneumococcal conjugate vaccine in children has been shown to reduce the incidence of IPD across all ages groups due to herd immunity, despite evidence of serotype replacement 30-33. Singapore introduced PCV7 into the National Childhood Immunisation Programme (NCIP) in October 2009 34, and this was switched to PCV13 in December 2011 17. The cost-effectiveness of childhood vaccination in the Singapore setting has been demonstrated by Tyo et al 35. Future studies are warranted to study the effectiveness of increasing PCV13 vaccination uptake, in both adults and children, to reduce incidence of invasive and non-invasive pneumococcal disease.
Finally, our study also demonstrated key factors associated with in-hospital mortality among pneumococcal patients. ICU admission was the strongest predictor, with those having admission being 23 times as likely as those who did not to die during their admission. Other factors included age ≥85yrs, higher Charlson’s score and diagnosis of IPD. Medical teams should especially note the increased mortality risk in these patients and ensure prompt management to reduce the risk of death.
The strengths of our study include a systematic selection of cases and controls among hospitalised patients. Furthermore, we followed up the patients longitudinally to the point of discharge from the hospital. Our study population is likely representative of patients hospitalised for pneumococcal disease in Singapore, as our hospital has a large catchment area which is not geographically restricted and patients from anywhere in Singapore may be admitted. Our findings are useful to guide the identification of patients at high risk of in-hospital mortality from the disease. They also support current recommendations to vaccinate at-risk individuals to prevent IPD.
Our study also has some limitations. Selection bias might have been present as clinicians may have preferentially ordered streptococcal urinary antigen and sterile site cultures for certain groups of patients, such as those who were elderly, with co-morbidities, or without records of recent vaccinations. At the time of the study, we had verified that there were no clinical protocols mandating such tests to be done for any particular patient groups. Our definition of cases included the use of results from streptococcal urinary antigen testing, which has an estimated sensitivity of 74.0% and specificity of 97.2% 36. Sterile site cultures from multiple possible sources (e.g. blood, joint fluid, or pleural fluid) will also have varying microbial culture methods with different sensitivity and specificity. Some cases of pneumococcal disease may hence have been misclassified as controls (i.e. false negatives). However, such a misclassification could have reduced the magnitude of our findings, but not negated them. As our data was obtained through hospital electronic medical records, clinical data from other sources (e.g. other hospitals or the primary care sector) were not available. However, majority of our patients tended to return back to our hospital if future admissions were required. Moreover, it is likely that this issue would result in non-differential misclassification (if any) as data would not be captured differently across study groups. We were unable to capture data for some known risk factors, such as smoking history and socioeconomic status. Our analysis of IPD cases was limited by the relatively small numbers, especially when divided into subgroups. Pneumococcal serotype data were also not available for this study, as this is not routinely performed for isolates. Nevertheless, we have reviewed data from serotyping studies conducted in the local setting 6, 10, 27, which we believe to be applicable to our study population. The generalisability of our study is limited to hospitalised adult patients.