Hostname: page-component-586b7cd67f-2brh9 Total loading time: 0 Render date: 2024-11-26T13:07:15.877Z Has data issue: false hasContentIssue false

Increased risk of invasive pneumococcal disease in haematological and solid-organ malignancies

Published online by Cambridge University Press:  30 April 2010

A. WONG*
Affiliation:
Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada
T. J. MARRIE
Affiliation:
Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada
S. GARG
Affiliation:
EPICORE Centre, University of Alberta, Edmonton, Alberta, Canada
J. D. KELLNER
Affiliation:
Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
G. J. TYRRELL
Affiliation:
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada The National Centre for Streptococcus, The Provincial Laboratory for Public Health (Microbiology), Edmonton, Alberta, Canada
*
*Author for correspondence: Dr A. Wong, Division of Infectious Diseases, University of Alberta, 2E4.16 Walter Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada T6G 2B7. (Email: [email protected])
Rights & Permissions [Opens in a new window]

Summary

Large-scale population-based studies have reported a significant increase in invasive pneumococcal disease (IPD) in those with underlying haematological or solid-organ malignancy, but limited condition-specific data are available on rates of IPD in the adult population. A retrospective chart review of all patients with IPD (identified prospectively) in the province of Alberta, Canada (population ~3·3 million) was conducted from 2000 to 2004 to study the epidemiology of IPD. Rates of IPD in patients with various haematological and solid-organ malignancies were determined by obtaining the number of these patients at risk from the provincial cancer registry. Compared to the attack rate of IPD in the adult population aged ⩾18 years (11·0 cases/100 000 per year, 95% CI 10·44–11·65), there were significantly increased rates of IPD in those with lung cancer (143·6 cases/100 000 per year, OR 13·4, 95% CI 9·3–19·4, P<0·001) and multiple myeloma (673·9 cases/100 000 per year, OR 62·8, 95% CI 39·6–99·8, P<0·001). More modestly increased rates of IPD were found in those with chronic lymphocytic leukaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, and Hodgkin's and non-Hodgkin's lymphoma. There was an increased prevalence of serotype 6A in those with these underlying malignancies, but no other serotypes predominated. Fifty-three percent (48/83) of cases were caused by serotypes in the investigational 13-valent pneumococcal conjugate vaccine (PCV13), and 57/83 (69%) of the cases were caused by serotypes in the 23-valent pneumococcal polysaccharide vaccine (PPV23). The incidence of IPD in adults with certain haematological and solid-organ malignancies is significantly greater than the overall adult population. Such patients should be routinely given pneumococcal polysaccharide vaccine; this population could also be targeted for an expanded valency conjugate vaccine.

Type
Original Papers
Copyright
Copyright © Cambridge University Press 2010

INTRODUCTION

Streptococcus pneumoniae is an important cause of community-acquired pneumonia, bacteraemia, and meningitis. Invasive pneumococcal disease (IPD) is defined as isolation of S. pneumoniae from a normally sterile body site (typically blood or cerebrospinal fluid), and carries with it significant morbidity and mortality, even in the modern antibiotic era. The mortality rate of pneumococcal bacteraemia in a large prospective international study was 16·9% in those with age >65 years and the presence of underlying disease or risk factors for immunosuppression significantly associated with increased mortality [Reference Yu1]. Pneumococcal meningitis also leads to poor outcomes, carrying a mortality rate of 21% [Reference Schuchat2]. Various states of immunodeficiency, including underlying malignancy, are recognized as risk factors for IPD [3, Reference Dworkin4]. Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is efficacious against IPD and recommended for patients in high-risk groups, including all patients with malignancy [Reference Moberley57]. Unfortunately, many patients with IPD who have an indication for vaccination are not vaccinated despite multiple encounters with the healthcare system [Reference Kyaw8].

Large-scale population studies have found increased rates of IPD in paediatric and adult patients with haematological and solid-organ malignancies [Reference Kyaw9Reference Hjuler11], but condition-specific data is lacking. We conducted a large 5-year retrospective study of all adult patients aged ⩾18 years with IPD in the province of Alberta and obtained provincial prevalence data for various malignancies from the Alberta Cancer Board to determine the rates of IPD in patients with selected underlying malignancies.

METHODS

Demographics and definitions

The study was conducted in the province of Alberta from 2000 to 2004, which at the time of the study was divided into nine health regions. The population was 2 967 755 in 2000 and 3 179 036 in 2004 [12]. Cases of IPD were defined as the isolation of S. pneumoniae from any normally sterile body site, including blood, cerebrospinal fluid, pleural fluid, biopsy tissue, synovial fluid, pericardial fluid, and peritoneal fluid [13]. In Alberta, IPD is a notifiable disease reportable to the Provincial Health Office. S. pneumoniae isolates recovered from patients with IPD are submitted to the National Centre for Streptococcus (NCS) located in Edmonton, Alberta, for capsular serotyping and antimicrobial resistance profiling for trending analysis. Isolates were submitted to the NCS prospectively from acute diagnostic microbiology laboratories in Alberta during the study period.

To ensure as complete as possible the capture of all patients with IPD in Alberta during the study period, a number of databases were utilized. These included all patients identified by identification of S. pneumoniae isolates sent to the NCS, all patients reported to the provincial health office, and all patients captured in both the Calgary area S. pneumoniae Research Group database (Calgary, AB) and the Community Acquired Pneumonia Study database (Edmonton, AB). All four databases were combined to form the final dataset, and duplicate patients (identified by personal health number) were counted only once. An extensive retrospective chart review of all identified patients was then performed for all identified IPD cases occurring during the survey period. Current underlying malignancies were recorded as described in the chart. Haematological malignancies were defined as any leukaemia, any lymphoma, or multiple myeloma.

In the laboratory, upon receipt of S. pneumoniae isolates, bacteria were stored at −70°C until serotyping and susceptibility assays were performed. Only one isolate from each IPD case was included in the review unless the isolates were collected ⩾1 month apart or were of a different serotype if <1 month had elapsed between episodes of IPD.

Annual incidence rates of IPD for the general population were calculated between 2000 and 2004 using provincial population estimates from Alberta Health and Wellness [12]. Condition-specific incidence rates of IPD between 2000 and 2004 were calculated based on annual prevalence data of haematological and solid-organ malignancies obtained from the provincial cancer registry, maintained by the Alberta Cancer Board [Reference Wang14]. The registry records all new cancer cases throughout the province and also tracks all cancer-related deaths using information from Alberta Vital Statistics and Statistics Canada. Malignancies considered in our study included lung cancer (small-cell and non small-cell), multiple myeloma, chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

The study received approval from the institutional research review committees of all nine health regions in Alberta and also from the University of Alberta and the University of Calgary.

Serotyping of S. pneumoniae isolates

Isolates received at the NCS were confirmed as S. pneumoniae based on morphology and optochin susceptibility [Reference Facklam, Washington, Balows, Hausler, Herrmann, Isenberg and Shadomy15]. Serotyping was performed at the NCS by Quellung reaction using commercial antisera prepared at the World Health Organization (WHO) Collaborating Center for Reference and Research on Pneumococci, located at the Statens Seruminstitut Copenhagen, Denmark [Reference Lund, Henrichsen, Bergan and Norris16]. Strains that failed to type were confirmed as S. pneumoniae using Accuprobe™ (Genprobe, USA).

Statistical analysis

Incidence rates and serotype prevalence were compared between various malignancies and the general adult population (all adults aged ⩾18 years) using Fisher's exact test. All statistical analyses were performed using SPSS version 16.0 (SPSS Inc., USA).

RESULTS

Incidence rates of IPD for patients with various malignancies vs. general population

A total of 1768 cases of IPD were identified in Alberta between 2000 and 2004 for which laboratory and clinical data were both complete. Of these cases 1273 occurred in patients aged ⩾18 years, for an incidence rate of 11·0 cases/100 000 population per year (95% CI 10·44–11·65). Of these, 152 (11·9%) cases occurred in adult patients with some form of underlying malignancy. Sixty-one (4·8%) cases involved patients with an underlying haematological malignancy, 82 (6·4%) cases involved patients with an underlying solid-organ malignancy (including cutaneous malignancies), and four (0·3%) occurred in patients who had haematological and solid-organ malignancies together. In the remaining five (0·4%) cases, the underlying malignancy was not classifiable based on the information in the database.

None of the four patients with haematological and solid-organ malignancies occurring together had lung cancer, hence these patients were grouped with their respective haematological malignancy in the final condition-specific analysis. Ten patients with haematological malignancy (six with lymphoma, four with leukaemia) were not able to be classified further based on information available from the database – these patients were not included in the condition-specific analysis. In total, 84 cases were included in the final condition-specific analysis, comprised of 29 patients with lung cancer and 55 patients with classifiable haematological malignancy.

The condition-specific incidence rates of IPD identified during the study period are given in Table 1 and compared to rates of IPD in the general adult population aged ⩾18 years. There was an increased risk of IPD in all six malignancies compared to the remainder of the general adult population aged ⩾18 years. With respect to the haematological malignancies, the risk of IPD steadily increased from patients with lymphoma (4·4 times greater with Hodgkin's, 5·8 times greater with non-Hodgkin's) to leukaemia (11·9 times greater with AML or ALL, 12·6 times greater with CLL), and was highest in those with multiple myeloma (62·8 times greater). There was a 13·4 times greater risk of IPD in those with lung cancer.

Table 1. Rates of invasive pneumococcal disease (IPD) in patients with underlying malignancy, 2000–2004

OR, Odds ratio; CI, confidence interval.

Pooled analysis of haematological malignancies including unclassifed cases

Given the number of unclassified haematological malignancies not included in the condition-specific analysis, we performed a pooled analysis which included these cases. Table 2 gives the results of a pooled analysis of all cases of lymphoma and leukaemia, including the 10 unclassified cases described above, as well as of all haematological malignancies together. The risk of IPD with any lymphoma was 7·5 times greater than the remainder of the general population aged ⩾18 years, which increased to 14·7 times greater with any leukaemia. A pooled analysis of all haematological malignancies including the 10 unclassifiable cases revealed an overall incidence rate of 142·1 cases/100 000 per year (95% CI 107·59–176·64), for a 13·6 times increased risk of IPD compared to the remainder of the adult population aged ⩾18 years (95% CI 10·63–17·50, P<0·001).

Table 2. Analysis of rates of invasive pneumococcal disease (IPD) in patients with haematological malignancies (including patients with unclassified haematological malignancies), 2000–2004

OR, Odds ratio; CI, confidence interval.

Demographic and clinical characteristics of patients with IPD and underlying malignancy

Selected demographic and clinical characteristics on the IPD cases in patients with underlying malignancy are provided in Table 3, organized by malignancy. Unclassified cases of lymphoma (six patients) and leukaemia (four patients) were also included. There were 26/29 (90%) patients with lung cancer and IPD that had a history of smoking, but in none of the other malignancies did rates of smoking exceed that of the general population aged ⩾18 years with IPD. Smoking history was not available in 19 cases. Eighty-five of the 94 (90%) patients had pneumococcal bacteraemia, eight had S. pneumoniae isolated from pleural fluid, and one had meningitis. Eighty-three of the 94 (88%) patients required admission to hospital, 10 of whom required admission to either an intensive care unit or coronary care unit setting, with the remaining 73 being admitted to a medical or surgical unit. Twenty-six of the 83 (31%) patients admitted to hospital died, with 20 (24%) of these cases being directly attributed to IPD or complications thereof. The remaining six patients who died were listed in the database as having died of other causes.

Table 3. Selected demographic and clinical characteristics of patients with invasive pneumococcal disease (IPD) and underlying malignancy

ICU/CCU, Intensive care unit/coronary care unit.

* Unclassified cases of lymphoma and leukaemia were included.

S. pneumoniae serotypes of isolates from cases of IPD with underlying malignancy

There was an increased prevalence of serotype 6A (11/84; 13% vs. 48/1273, 4%, OR 4·7, 95% CI 2·3–9·5, P<0·001) compared to the general adult population aged ⩾18 years, but no other serotypes predominated. Six cases were caused by serotype 9V and five cases by each of serotypes 3, 4, 6B, 19F, and 23F. Four cases were caused by each of serotypes 8, 22F, and 35B. Two cases were caused by each of serotypes 9N, 10A, 11A, 12F, 18C, 23A, 33F, and 38. A single case was caused by each of serotypes 1, 7F, 9L, 13, 14, 15A, 15B, 15C, 17F, 19A, 23B, and 35A. Serotype data was not available in two cases.

Twenty-nine (35%) cases were caused by serotypes in the 7-valent conjugate vaccine (PCV7, Prevnar®, Wyeth, USA), 31 (37%) cases were caused by serotypes in the 10-valent conjugate vaccine (PCV10, Synflorix®, GlaxoSmithKline, USA) and 48 (57%) cases were caused by serotypes in the 13-valent conjugate vaccine (PCV13, Prevnar 13). Fifty-seven (69%) cases were caused by serotypes in the 23-valent polysaccharide vaccine (PPV23, Pneumovax® 23, Merck, USA).

DISCUSSION

A 2005 study from the USA estimated the incidence of IPD in patients with haematological malignancy at 503·1 cases/100 000 per year (95% CI 272·6–334·6) and for solid-organ malignancy at 300·4 cases/100 000 per year (95% CI 422·2–622·3). There was a 38·3 times greater risk for patients with haematological malignancy and a 22·9 times greater risk for those with solid-organ malignancy compared to that of healthy adults [Reference Kyaw9]. Data from Scotland revealed increased rates of IPD in patients with haematological malignancy (733·7 cases/100 000 per year) and non-haematological malignancy (216·1 cases/100 000 per year) [Reference Kyaw10]. Data on the incidence of IPD in adults with specific underlying malignancies is limited, although a recent study from Germany found a 10 times greater risk of IPD in children with ALL [Reference Meisel17].

In our 5-year retrospective analysis, we identified 29 cases of IPD in patients with lung cancer in the province of Alberta between 2000 and 2004, a 13·4 times greater incidence of IPD compared to the remainder of the adult population aged ⩾18 years. If lung cancer is considered a surrogate for solid-organ malignancy, the incidence rate and odds ratio calculated in our study are lower than results previously estimated for solid-organ malignancies [Reference Kyaw9, Reference Kyaw10].

In our study, the highest rates of IPD were found in patients with multiple myeloma, who had a 62·8 times greater risk compared to the remainder of the general population aged ⩾18 years. Patients with multiple myeloma have been well-described as being at increased risk of bacterial infections with both Gram-positive and Gram-negative organisms, although the reasons for this have not been clearly elucidated [Reference Salonen and Nikoskelainen18]. Multiple myeloma leads to defects in complement activation and neutrophil function, as well as functional hypogammaglobulinaemia [Reference Jacobson and Zolla-Pazner19]. Decreased CD4 counts and decreased CD4/CD8 ratios have also been found in patients with multiple myeloma [Reference Pilarski20]. More modestly increased rates of IPD were found in patients with other haematological malignancies including lymphoma, CLL, and AML/ALL. The overall rate in patients with underlying haematological malignancy of 142·1 cases/100 000 per year is less than has been previously reported [Reference Kyaw9, Reference Kyaw10].

Serotype 6A, which was the only serotype to have an increased prevalence compared to the general adult population, is one of the six serotypes included in PCV13 but not in PCV7 or PCV10. Overall, 19/152 (12·5%) cases of IPD in patients with underlying malignancy were caused by one of the six serotypes included in PCV13 but not PCV7 or PCV10. The use of PCV13 directly in this high-risk population as well as in children may confer beneficial protective effects against IPD in patients with underlying malignancy via both direct and indirect (‘herd’) effects [Reference Musher21].

There are limitations to our study. We only captured patients with a positive isolate, and it is possible that cases of IPD were missed if cultures were not done or if they were negative (e.g. if drawn after the administration of antibiotics). Mortality rates reflect patients who died in hospital only. We relied on documentation of malignancy on the patient's chart, and it is possible that cases were missed because a patient's medical history was not documented. In some cases not enough detail was provided in the chart (i.e. only ‘lymphoma’ or ‘leukaemia’ were reported) to classify patients into the appropriate condition-specific groups for analysis. Hence, our study provides a minimal estimate of the risk of IPD and the actual risk may be higher. Pneumococcal vaccination status of patients could not be accounted for in our study. Age and smoking status may have confounded results, as may have other factors not accounted for in this study.

Our study reinforces that the risk of IPD is significantly increased in lung cancer and various haematological malignancies, and a systemic PPV23 vaccination strategy among those providers who care for these patients should be considered. Evaluation of an expanded valency conjugate vaccine in this high-risk population via prospective studies is warranted.

ACKNOWLEDGEMENTS

We acknowledge the staff of the Acute Diagnostic Microbiology Laboratories in Alberta who submitted isolates from cases of IPD to the National Centre for Streptococcus, Edmonton, Alberta. We acknowledge the contributions of Carol Mangan, Stephanie Hui, Linda Hastie, and the efforts of the Data Collection Team who include Anne Witschen, Lynne Korobanik, Freda Anderson, Loy Bacon, Shannon Pyra, Janine Schouten, Ambreen Mithani, and Natalie Chui. We also thank Janice Pitchko for designing and maintaining the study databases and Heather Mangan for her assistance with the database.

The procurement of the laboratory data for this work was supported by Alberta Health & Wellness (Edmonton, AB) and the National Microbiology Laboratory (Winnipeg, MB). This research was funded by the Provincial Laboratory for Public Health (Edmonton, AB) and a grant-in-aid from Wyeth Canada (Toronto, ON). The funders had no role in the study design or implementation, interpretation of data, analysis or manuscript preparation.

DECLARATION OF INTEREST

T.J.M., J.D.K., and G.J.T. have received compensation from Wyeth for consulting and speaking about pneumococcal vaccination, and financial support from Wyeth for performing epidemiological analyses of cases of invasive pneumococcal disease in the province of Alberta.

References

REFERENCES

1.Yu, VL, et al. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clinical Infectious Diseases 2003; 37: 230237.CrossRefGoogle ScholarPubMed
2.Schuchat, A, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. New England Journal of Medicine 1997; 337: 970976.CrossRefGoogle ScholarPubMed
3.Centers for Disease Control and Prevention (CDC). Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 1997; 46: 1.Google Scholar
4.Dworkin, MS, et al. Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination. Clinical Infectious Diseases 2001; 32: 794800.CrossRefGoogle ScholarPubMed
5.Moberley, SA, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database of Systematic Reviews 2008; Issue No. 1. Art. No. CD000422.CrossRefGoogle ScholarPubMed
6.Centers for Disease Control and Prevention (CDC). Recommended adult immunization schedules – United States, 2008. Morbidity and Mortality Weekly Report 2007; 56: 1.Google Scholar
7.Public Health Agency of Canada. Pneumococcal vaccine. In: Canadian Immunization Guide, 7th edn. Ottawa: Public Health Agency of Canada, 2006, pp. 267276.Google Scholar
8.Kyaw, MH, et al. Adults with invasive pneumococcal disease: missed opportunities for vaccination. American Journal of Preventive Medicine 2006; 31: 286292.CrossRefGoogle ScholarPubMed
9.Kyaw, MH, et al. The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults. Journal of Infectious Diseases 2005; 192: 377386.CrossRefGoogle ScholarPubMed
10.Kyaw, MH, et al. Invasive pneumococcal disease in Scotland, 1999–2001: use of record linkage to explore associations between patients and disease in relation to future vaccination policy. Clinical Infectious Diseases 2003; 37: 12831291.CrossRefGoogle ScholarPubMed
11.Hjuler, T, et al. Risks of invasive pneumococcal disease in children with underlying chronic diseases. Pediatrics 2008; 122: e26–32.CrossRefGoogle ScholarPubMed
12.Alberta Health and Wellness (AH&W).Population Projections for Alberta and its Health Regions, 2000–2030. Edmonton: AH&W, 2001.Google Scholar
13.Health Canada. Case definitions for diseases under national surveillance. Canadian Communicable Disease Report 2000; 26: S3S51.Google Scholar
14.Wang, M.Surveillance analyst, Alberta Cancer Board, personal communication, 21 February 2008.Google Scholar
15.Facklam, RR, Washington, JA. Streptococcus and related catalase-negative gram-positive cocci. In: Balows, A, Hausler, WJ, Herrmann, KL, Isenberg, HD, Shadomy, HJ, eds. Manual of Clinical Microbiology, 5th edn. Washington, DC: American Society for Microbiology, 1991, pp. 238257.Google Scholar
16.Lund, R, Henrichsen, J. Laboratory diagnosis, serology and epidemiology of Streptococcus pneumoniae. In: Bergan, T, Norris, JR, eds. Methods in Microbiology, vol. 12. New York: Academic Press Inc., 1978, pp. 241262.Google Scholar
17.Meisel, R, et al. Increased risk for invasive pneumococcal disease in children with acute lymphoblastic leukaemia. British Journal of Haematology 2007; 137: 457460.CrossRefGoogle ScholarPubMed
18.Salonen, J, Nikoskelainen, J. Lethal infections in patients with hematological malignancies. European Journal of Haematology 1993; 51: 102108.CrossRefGoogle ScholarPubMed
19.Jacobson, DR, Zolla-Pazner, S. Immunosuppression and infection in multiple myeloma. Seminars in Oncology 1986; 13: 282290.Google ScholarPubMed
20.Pilarski, LM, et al. Comparative analysis of immunodeficiency in patients with monoclonal gammopathy of undetermined significance and patients with untreated multiple myeloma. Scandinavian Journal of Immunology 1989; 29: 217228.CrossRefGoogle ScholarPubMed
21.Musher, DM. Pneumococcal vaccine – direct and indirect (‘herd’) effects. New England Journal of Medicine 2006; 354: 15221524.CrossRefGoogle ScholarPubMed
Figure 0

Table 1. Rates of invasive pneumococcal disease (IPD) in patients with underlying malignancy, 2000–2004

Figure 1

Table 2. Analysis of rates of invasive pneumococcal disease (IPD) in patients with haematological malignancies (including patients with unclassified haematological malignancies), 2000–2004

Figure 2

Table 3. Selected demographic and clinical characteristics of patients with invasive pneumococcal disease (IPD) and underlying malignancy