Streptococcus pneumoniae causes a wide range of diseases that include middle ear infection, sinusitis, pneumonia, and meningitis. As one of the most common pathogens in community-acquired pneumonia (especially in Western countries), S pneumoniae infection contributed to 1.6 million deaths in 2010 and 3.7 million severe pneumococcal infections worldwide in 2015.1 2 3

Streptococcus pneumoniae is a gram-positive encapsulated bacterium that colonises human nasopharynx and is mainly transmitted via respiratory droplets, which cause middle ear and respiratory tract infection. Thus far, more than 90 serotypes of S pneumoniae have been identified. Streptococcus pneumoniae infection can be stratified into invasive and non-invasive disease.4 5 Invasive pneumococcal disease (IPD) is a notifiable disease in Hong Kong. In 2019, there were 187 cases; the incidence has remained similar over the past few years.6 Worldwide, there is growing concern regarding drug-resistant S pneumoniae strains (eg, strains resistant to macrolide, penicillin, and/or fluoroquinolone). However, drug-resistant strains have not been associated with higher mortality rates.7 The prevalence of drug-resistant S pneumoniae is lower in Southeast Asia than in Western countries.1 Despite inconclusive evidence in the literature regarding its association with mortality, IPD is often associated with more severe disease and requires more invasive organ support.8

In this study, we aimed to identify the predictors for 30-day mortality in patients with S pneumoniae infection, as well as predictors for IPD. We also performed subgroup analysis of patients in the intensive care unit (ICU) and identified risk factors for 30-day mortality and IPD in those patients, as well as all patients with S pneumoniae infection.

This retrospective cohort study included adults who were admitted to Pamela Youde Nethersole Eastern Hospital, Hong Kong, with pneumococcal infection from 1 January 2011 to 31 December 2018. Patients who were aged <18 years or had incomplete data were excluded.

Patient medical records and data were extracted from clinical management systems and clinical information systems (IntelliVue Clinical Information Portfolio; Philips Medical, Amsterdam, The Netherlands). Baseline demographics, clinical characteristics, and microbiological data were identified. For patients in the ICU, disease severity was quantified using APACHE (Acute Physiology and Chronic Health Evaluation) IV scores. The use of invasive organ support was recorded, including continuous renal replacement therapy, inotropes, invasive mechanical ventilation, and extracorporeal membrane oxygenation. The primary outcome was 30-day all-cause mortality; secondary outcomes were ICU and hospital mortalities, ICU and hospital length of stay (LOS), and ICU ventilator days.

Pneumococcal infection was determined by positive culture of S pneumoniae. Invasive pneumococcal disease was defined as the presence of S pneumoniae in sterile sites (eg, pleural fluid, cerebrospinal fluids, and blood).4 8 Non-invasive pneumococcal disease was defined as the presence of S pneumoniae in non-sterile sites, or a positive urinary antigen test (UAT) result. Medical co-morbidities (eg, diabetes mellitus, chronic kidney disease, heart failure, and haematological malignancies) were coded in accordance with the International Classification of Diseases, Ninth Revision, Clinical Modification. Smokers were defined as those who had ever smoked. Advanced age was defined as age >65 years.

Antibiotic resistance was determined based on Clinical and Laboratory Standards Institute testing criteria for minimal inhibitory concentrations. Breakpoints adopted for determination of parenteral penicillin resistance in non-meningitis S pneumoniae isolates were susceptible, ≤2 μg/mL; intermediate, 4 μg/mL; and resistance, ≥8 μg/mL.9 Breakpoints adopted for determination of parenteral penicillin resistance in meningitis S pneumoniae isolates were susceptible, ≤0.06 μg/mL and resistance, ≥0.12 μg/mL; breakpoints adopted for determination of levofloxacin resistance in S pneumoniae were susceptible, ≤2 μg/mL; intermediate, 4 μg/mL; and resistance, ≥8 μg/mL.9

Urinary antigen test (Alere 710-012 BinaxNOW Streptococcus) results were evaluated in accordance with the manufacturer’s instructions.

Characteristics and clinical parameters were compared between patients with IPD and those with non-invasive pneumococcal disease, as well as between 30-day survivors and non-survivors. Results were expressed as median (interquartile range) or as numbers (percentages) of cases, as appropriate. For univariate analysis, categorical variables were compared by Pearson Chi squared tests or Fisher’s exact test, as appropriate; continuous variables were compared by using the Mann-Whitney U test. Variables with P<0.2 in univariate analysis or with known clinical significance from previous studies were entered into multivariate analysis. Independent predictors for 30-day mortality and independent predictors for IPD were assessed by logistic regression analysis.8 10 11 12 Subgroup analysis was performed regarding IPD and disease severity among patients in the ICU. Hosmer-Lemeshow test was performed for goodness-of-fit for logistic regression models. Kaplan-Meier survival plots were used to compare cumulative survival between patients with IPD and those with non-invasive pneumococcal disease. SPSS (Mac version 24.0; IBM Corp, Armonk [NY], United States) was used for all statistical analyses.

Patient demographic and clinical characteristics, including co-morbidities and use of invasive organ support, are shown in Table 1. In total, 792 patients with pneumococcal disease were identified during the 8-year study period. The median age was 73 years; patients were predominantly men. Most patients exhibited respiratory tract infection (96.1%) and approximately one quarter of patients had asthma/chronic obstructive pulmonary disease (24.4%). In total, 170 patients received intensive care and 14.1% required invasive mechanical ventilation; 28% required vasopressor use. Invasive pneumococcal disease was present in 13.4% of the patients. The overall hospital mortality rate was 11.2%, while the mortality rate among patients in the ICU was 22.9%.

Invasive pneumococcal disease was associated with a higher 30-day mortality rate (28.6% vs 11.4%, P<0.001); a positive UAT result was also associated with a higher 30-day mortality rate (36.3% vs 12.7%, P<0.001). Logistic regression analysis identified statistically significant predictors for 30-day mortality, which are shown in Table 1. Patients with vasopressor use (odds ratio [OR]=4.96, P<0.001), chronic kidney disease (OR=3.62, P<0.001), a positive UAT result (OR=2.57, P=0.001), and older age (OR=2.19, P=0.010) exhibited comparatively higher 30-day mortality rates; however, asthma/chronic obstructive pulmonary disease was not an independent predictor for mortality in logistic regression analysis. The Figure depicts the results of Kaplan-Meier survival analysis comparing patients with IPD and those with non-invasive pneumococcal disease.

Table 2 shows the characteristics of patients with IPD and those with non-invasive pneumococcal disease. More patients with asthma/chronic obstructive pulmonary disease exhibited non-invasive pneumococcal disease (26.5% vs 10.4%, P<0.001). Invasive pneumococcal disease was more likely to be associated with renal failure (27.4% vs 9.6%, P<0.001) and haematological malignancy (5.7% vs 1.7%, P=0.012). Additionally, IPD was associated with higher rates of ICU admission (33.0% vs 19.7%, P=0.002), renal replacement therapy (16.0% vs 4.8%, P<0.001), and vasopressor use (93.4% vs 17.9%, P<0.001). Patients with IPD had a higher 30-day mortality rate (24.5% vs 9.5%, P<0.001) and longer hospital LOS (8 vs 4 days, P<0.001). Independent risk factors for IPD by logistic regression analysis are shown in Table 2, along with their ORs. Notably, chronic kidney disease (OR=3.10, P<0.001) was the sole independent predictor for IPD.

The results of ICU subgroup analysis are shown in Table 3. Respiratory tract infection constituted 93.5% of all S pneumoniae infections. The rate of IPD was 20.6% among patients in the ICU with S pneumoniae infection, which was higher than the rate among all patients with S pneumoniae infection. Further analysis revealed that IPD was associated with higher rates of complications and invasive organ support; in particular, more patients with IPD required renal replacement therapy (48.6% vs 24.4%, P=0.005) and vasopressor use (100% vs 88.9%, P=0.039). Additionally, more patients with IPD tended to exhibit pleural effusion/empyema, although this difference was not statistically significant. Patients who required invasive mechanical ventilation (76.0% vs 57.5%, P=0.023), extracorporeal membrane oxygenation (14.0% vs 5.0%, P=0.044), renal replacement therapy (48.0% vs 21.7%, P=0.001), and vasopressor use (98.0% vs 88.3%, P=0.043) exhibited significantly higher 30-day mortality rates. Logistic regression analysis showed that chronic kidney disease (OR=4.64, P<0.001), higher APACHE IV score (OR=3.73, P=0.016), and a positive UAT result (OR=2.94, P=0.008) were independent predictors for 30-day mortality among patients in the ICU who had IPD (Table 3).

The overall mortality rate was 28.6% for patients with IPD and 11.4% for patients without IPD. The case fatality rate in our cohort was higher than that in a previous cohort from the Netherlands, but similar to the rate in a previous study from Korea.5 13 A higher number of co-morbid diseases, worse immune function, impaired mucociliary clearance, and older age are associated with a higher risk of mortality in patients with pneumococcal infection.4

Chronic conditions such as chronic lung disease, heart failure, and diabetes, as well as smoking status, were previously shown to be associated with pneumococcal disease and IPD.10 11 Consistent with the results of prior studies, we found that patients with heart failure (8.8% vs 3.3%, P=0.011) and haematological malignancies (5.7% vs 1.7%, P=0.012) exhibited significantly higher 30-day mortality rates in univariate analysis. Surprisingly, we found a negative association between chronic lung disease and mortality. In post-hoc analysis, we found that patients with chronic lung disease (ie, asthma/chronic obstructive pulmonary disease) also had a lower rate of invasive organ support (15.0% vs 32.7%, P<0.001). This group of patients may be under constant medical surveillance; thus, they may seek medical attention and receive antibiotics earlier than patients without chronic lung disease. Importantly, we did not examine the management and status of underlying lung conditions, which may have affected mortality in these patients.

In our cohort, 122 patients were diagnosed with pneumococcal infection by using the UAT. In our hospital, the first patient was diagnosed by using the UAT in 2015. Use of the UAT in diagnosing community-acquired pneumonia has since increased; thus, in 2018, 71 of 146 patients (48.6%) were diagnosed by using the UAT. A positive UAT result was a consistent independent predictor for 30-day mortality among patients in the ICU, as well as among all patients. Post-hoc analysis showed that a positive UAT result was significantly associated with ICU admission (34.7% vs 10.1%, P<0.001). However, it was not significantly associated with ICU LOS (6.16 vs 8.43 days, P=0.515) or hospital LOS (21.46 vs 29.78 days, P=0.415).

The pneumococcal UAT assay detects the C-polysaccharide antigen of S pneumoniae, which is present in all serotypes, from urine samples.14 Fluorescence immunoassay and immunochromatographic test methods provide similar results in terms of diagnosing pneumococcal disease.15 While the UAT result remains positive for up to 3 days after initiation of antibiotic treatment, the UAT increases the diagnostic yield of pneumococcal disease relative to the yield of sputum culture of S pneumoniae; notably, the yield of such sputum cultures markedly decreases after initiation of antibiotic treatment.16 This test provides a rapid and simple method for diagnosis of patients with suspected S pneumoniae infection; it is particularly helpful in the diagnosis of patients who cannot produce sputum for cultures. The test sensitivity and specificity were approximately 60% and 99%, respectively.16 Because of the high test specificity, the UAT helps to reduce the costs of further diagnostic tests and aids in selection of empirical antibiotic treatment. It is recommended in the Infectious Diseases Society of America/American Thoracic Society guidelines for aiding the rapid identification of pneumococcal disease in adults.17 Urinary antigen tests were also found to predict the severity and outcomes of pneumonia. A Korean group found that patients with positive UAT results exhibited greater severity of disease; however, the test results were associated with rates of ICU admission and mortality.14

Counterindications for the UAT include recent pneumococcal disease within 3 months; moreover, it may cross-react with antigens from other streptococcal bacteria.16 18 Patients with acute kidney injury due to sepsis, as well as those with oliguria or anuria of various aetiologies may not be able to provide urine samples for use in the UAT.

In our cohort, IPD was associated with a higher 30-day mortality rate; however, this association did not remain statistically significant in logistic regression analysis. Consistent with the results of previous studies,8 12 we found that patients with IPD exhibited more severe disease and worse outcomes. Moreover, IPD was associated with higher rates of ICU admission, invasive organ support (ie, vasopressor use), and renal replacement therapy, as well as longer hospital LOS. The findings might be explained by the higher bacterial load in patients with IPD, which may lead to worse outcomes.

Similar to the study by Ceccato et al,8 we did not identify a positive relationship between smoking and IPD. Thus far, results regarding the relationship of smoking with IPD have been inconsistent; the association varies according to local smoking prevalence.11 With the implementation of effective smoking cessation programmes and corresponding legislation in Hong Kong, approximately 10% of individuals >15 years of age report daily cigarette consumption; this is markedly lower than the rates in other countries.19 20 In our study, smoking status information was extracted from patient records stored in the Hospital Authority Clinical Management System and nursing notes; thus, we may have underestimated the number of smokers in this cohort. Other important aspects of smoking (eg, number of pack-years and passive smoking) were not available for inclusion in this analysis.

Chronic kidney disease has been consistently associated with IPD. A large retrospective observational cohort of 36 million adults revealed a risk ratio of 21.67 for development of IPD among patients with chronic kidney disease.21 A Japanese registry showed that the relative risk for IPD among patients with chronic kidney disease ranged from 12.4 to 51.3.10 Notably, chronic kidney disease was consistently one of the most important predictors for 30-day mortality among all patients (OR=3.62, P<0.001) and among patients in the ICU (OR=4.64, P<0.001).

Patients with IPD tended to experience a higher rate of complications and require higher rates of invasive organ support. In particular, patients with IPD more frequently exhibited pleural effusion/empyema; they also more frequently required invasive mechanical ventilation, extracorporeal membrane oxygenation, renal replacement therapy, and vasopressor use. Our sample size may not have been sufficiently powered to demonstrate statistically significant results regarding the ICU subgroup; thus, future studies focused specifically on patients in the ICU may be needed. Other aspects of IPD and use of rescue therapies for acute respiratory distress syndrome (eg, prone ventilation, muscle paralytic agents, and inhaled nitrogen oxide) should be investigated in the future.

Penicillin non-susceptible S pneumoniae was not common in the present study; it was only observed in 2.4% of patients. Non-susceptibility to levofloxacin was observed in 0.9% of patients. Drug non-susceptible S pneumoniae were not significantly associated with 30-day mortality (penicillin non-susceptible S pneumoniae was present in two non-survivors and 14 survivors, P=0.641; levofloxacin non-susceptible S pneumoniae was present in zero non-survivors and six survivors, P=1.000). However, these results should be carefully interpreted, because of the small number of drug non-susceptible S pneumoniae in our cohort. According to a recent study in Hong Kong, the penicillin resistance rate was approximately 7% and the levofloxacin resistance rate was 0%.22

Viral-bacterial interactions have been described with respect to pneumococcal disease.23 An epidemiological study regarding the 2009 H1N1 influenza pandemic period showed a significant increase in the number of pneumococcal pneumonia hospitalisations.24 However, viral co-infection was not associated with IPD or mortality in our findings. Notably, an age-specific interaction was described between influenza and IPD; specifically, patients aged 5 to 19 years were significantly more frequently affected, compared with other age-groups.24 25

Thus far, this is the first and largest study regarding pneumococcal disease in adults in Hong Kong; it provides clinical and outcome data in both general ward and intensive care subgroups to allow a comprehensive overview of pneumococcal disease in the locality. It is a standard practice in our centre to check urinary antigens and perform blood cultures for nearly all patients with suspected pneumonia to facilitate accurate diagnosis and avoid missed diagnoses. By including data regarding invasive organ support and ICU admission, we were able to identify and describe complications of pneumococcal disease and determine the broader clinical characteristics of affected patients.

However, because of changes in vaccination programmes, the influenza and pneumococcal vaccination statuses were not available for analysis in the current study. Because of the limited number of patients with drug non-susceptible S pneumoniae in the present cohort, further robust analyses regarding antibiotic sensitivity patterns and appropriateness of antimicrobial treatment could not be performed. Furthermore, capsular serotypes of S pneumoniae among patients in our cohort were not available for analysis. Future studies focused on capsular subtypes of S pneumoniae will facilitate understanding of pneumococcal disease. Because this was a retrospective study, it was subject to potential confounding factors. Finally, the results of this single-centre study may not be generalisable to other countries with higher prevalences of drug non-susceptible S pneumoniae infection.

Pneumococcal disease is associated with high rates of morbidity and mortality. In this cohort, vasopressor use, chronic kidney disease, advanced age, and positive UAT results were predictors for 30-day mortality.

Concept or design: MY Man, HP Shum.
Acquisition of data: MY Man, HP Shum.
Analysis or interpretation of data: MY Man, HP Shum.
Drafting of the manuscript: MY Man, A Wu.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

The abstract of this study was accepted as an oral presentation at the Annual Scientific Meeting of the Hong Kong Society of Critical Care Medicine on 8 December 2019.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approval by the Hospital Authority Hong Kong East Cluster Research Ethics Committee (Ref HKECREC- 2019-065). The requirement for written informed consent was waived.

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