Abstract

Background. The 13-valent pneumococcal conjugate vaccine (PCV13) has recently been approved for use in immunocompromised adults. However, it is unclear whether there is an association between specific underlying conditions and infection by individual serotypes. The objective was to determine the prevalence of serotypes covered by PCV13 in a cohort of patients with invasive pneumococcal disease of respiratory origin and to determine whether there are specific risk factors for each serotype.

Methods. An observational study of adults hospitalized with invasive pneumococcal disease in 2 Spanish hospitals was conducted during the period 1996–2011. A multinomial regression analysis was performed to identify conditions associated with infection by specific serotypes (grouped according their formulation in vaccines and individually).

Results. A total of 1094 patients were enrolled; the infecting serotype was determined in 993. In immunocompromised patients, 64% of infecting serotypes were covered by PCV13. After adjusting for age, smoking, alcohol abuse, and nonimmunocompromising comorbidities, the group of serotypes not included in either PCV13 or PPV23 were more frequently isolated in patients with immunocompromising conditions and cardiopulmonary comorbidities. Regarding individual serotypes, 6A, 23F, 11A, and 33F were isolated more frequently in patients with immunocompromise and specifically in some of their subgroups. The subgroup analysis showed that serotype10A was also associated with HIV infection.

Conclusions. Specific factors related to immunocompromise seem to determine the appearance of invasive infection by specific pneumococcal serotypes. Although the coverage of serotypes in the 13-valent conjugate pneumococcal vaccine (PCV13) was high, some non-PCV13-emergent serotypes are more prevalent in immunocompromised patients.

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia in adults and a major cause of morbidity and mortality worldwide [1]. In specific groups of patients with different underlying conditions, such as comorbidities, immunocompromise, and aging, the prevalence of pneumococcal disease is clearly increased [2].

Active immunization is one of the key interventions to reduce the burden of pneumococcal disease. The 23-valent pneumococcal polysaccharide vaccine (PPV23) was licensed in 1983 with this purpose. However, its effectiveness in pediatric and immunocompromised populations, and in elderly subjects, has been questioned [3–5].

Pneumococcal conjugate vaccines (PCVs) have been shown to be immunogenic and preventive of pneumococcal disease in children, even in immunocompromised patients [6]. The introduction of a PCV with 7 pneumococcal serotypes (PCV7) for children in 2000 has produced a significant reduction of pneumococcal disease in children, and, indirectly, in adults [7]. In Spain, PCV7 was introduced in June 2001, and in 2006 vaccine coverage reached up to 45% of the children in the study area [8]. The dramatic reduction of PCV7 serotype disease in adults after the introduction of this vaccine reinforced the hypothesis that children are both reservoirs and vectors for adult pneumococcal disease.

In June 2012, the Advisory Committee on Immunization Practices (ACIP) recommended the routine use of a 13-valent pneumococcal conjugate vaccine (PCV13) for adults with immunocompromising conditions [9]. There is evidence, however, that individual serotypes of Streptococcus pneumoniae not only have different clinical manifestations, but also different target populations [10, 11], and the effects of PCV13 may vary substantially depending on the characteristics of the patient. Lack of data about baseline conditions related to age, comorbidities, and immune status associated with infection by individual pneumococcal serotypes in a specific patient is a major barrier to predict the protective effect of PCV13 for adult pneumococcal disease.

In view of the possible differences in the prevalence of pneumococcal serotypes according to patient characteristics, the aim of the study was to determine the frequency of serotypes covered by PCV13 in patients with invasive pneumococcal disease of respiratory origin, and to study the specific underlying conditions associated with infection by the most prevalent individual pneumococcal serotypes in these patients.

MATERIALS AND METHODS

Design and Study Population

Patients were enrolled as part of an observational study initiated in January 1996 that included all adults (aged ≥18 years) hospitalized for invasive pneumococcal disease of respiratory origin in 2 teaching hospitals from Catalonia, Spain (Hospital Universitari Vall d'Hebron [Barcelona] and Hospital Universitari Parc Tauli [Sabadell]) until December 2011, for an overall study period of 16 years. All strains recovered from blood and pleural fluid of patients with a respiratory infection showing positive cultures for S. pneumoniae were considered for the study. Informed consent for the study was waived due to its observational design.The study was approved by the ethics boards of both hospitals. A subset of the participating patients has been included in another study to determine the association between pneumococcal serotypes and empyema [10].

Study Variables and Definitions

For all patients the following variables were recorded: sociodemographic data (age, sex, current smoking, long-term alcohol abuse, and vaccination status with the 23-valent pneumococcal polysaccharide vaccine [PPV23]), comorbidities, immunocompromising conditions, and microbiological data (serotype and antibiotic resistance pattern of the S. pneumoniae causal strain).

Participating patients were considered smokers when they had smoked >10 cigarettes per day for at least 1 year, and alcohol abuse was defined as a daily consumption of alcohol >80 g for at least 1 year. A patient was considered vaccinated for pneumococcal infection if PPV23 vaccine had been administered according to the hospital and primary healthcare center records. For the purposes of the study, comorbidities were defined and included as follows: chronic lung (chronic obstructive pulmonary disease [COPD] or interstitial lung disease); cardiac (congestive heart failure, cardiac ischemia, or valvulopathy); renal (chronic renal failure); liver (hepatic cirrhosis); and neurological disease (cerebrovascular disease or dementia).

Immunocompromising conditions included the following groups: primary immunodeficiency, human immunodeficiency virus [HIV] infection, anatomical or functional asplenia, active hematological or advanced solid cancer, current immunosuppressive therapy including corticosteroid therapy (>8 mg/d methylprednisolone or equivalent), and chemotherapy and/or radiation therapy in the previous 3 months. Immunocompromised patients were classified in the following groups: HIV infection, solid cancer, hematologic cancer, chronic corticosteroid therapy, and nonsteroid immunosuppressive therapy.

Invasive pneumococcal disease of respiratory origin was diagnosed when a patient had clinical findings consistent with this diagnosis and a new pulmonary infiltrate on the chest radiography, with isolation of S. pneumoniae in blood and/or pleural fluid cultures.

Microbiological Procedures

Streptococcus pneumoniae strains were identified by Gram staining, Optochin susceptibility, bile solubility, and latex agglutination testing. Serotypes were identified by capsular swelling reaction using commercial serogroup and serotype-specific antisera and the Quellung reaction at the Spanish Reference Laboratory (Instituto de Salud Carlos III, Madrid). Antimicrobial susceptibility was tested using the microdilution method in accordance with Clinical and Laboratory Standards Institute procedures [12]. For the purpose of the study, serotypes were classified in 2 different ways. In the first analysis, they were classified into 3 groups according to their inclusion in the commercial vaccines: (1) serotypes in the PCV13 vaccine (the serotypes part of the former PCV7 [4, 6B, 9V, 14, 18C, 19F, 23F], with the 6 newly added serotypes [1, 3, 5, 6A, 7F, 19A]); (2) serotypes in PPV23 not present in PCV13 (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F); and (3) serotypes not included in PPV23 or in PCV13. In a second analysis, serotypes with >10 isolates were analyzed separately.

Estimation of Incidence of Infection by Groups of Serotypes

The proportion of pneumococcal infection by groups of serotypes based on their inclusion in the vaccine formulations was determined. The period 1996–2002 was grouped, as it was considered to be representative of the situation before the introduction of PCV7 in Spain [10], and in the post-PCV7 era (2003–2011), the proportion and incidence of the different serotypes was analyzed yearly, considering them as representative of the period previous to the commercial introduction of PCV13. Finally, the incidence of infection due to PCV7 and PCV13 serotypes, and the serotypes not included in PCV13, defined as the number of episodes per 100 000 inhabitants per year, was calculated using the number of adults living in the referral areas of the 2 hospitals participating in the study as the denominator, from data obtained from the Catalan Department of Statistics [13].

Statistical Analysis

Data were analyzed using the SPSS statistical software package, version 19 (SPSS Inc, Chicago, Illinois). Results for categorical variables are expressed as absolute and relative frequencies and results for continuous variables as the mean and standard deviation (SD).

First, factors associated with baseline conditions were studied grouping the serotypes into 3 different categories: serotypes included in PCV13 formulation (as a whole and subdivided into PCV7 and the 6 newly added PCV13 serotypes), serotypes included in PPV23 and not in PCV13, and serotypes not included in either formulation. Categorical variables were compared using the χ2 test or Fisher exact test as necessary and continuous variables by means of analysis of variance. A multinomial regression analysis was performed with the same classification, with the PCV13 serotypes acting as a reference category. In a parallel model, the PCV13 serotypes were subdivided into PCV7 serotypes and the 6 new serotypes part of PCV13; in this model the PCV7 serotypes acted as a reference category. The validity of the model was assessed by the ratio percentage accuracy rate/(chance accuracy × 1.25), considering it to be appropriate when the ratio was >1. Multicollinearity in the model was assessed by means of standard error coefficients, considering that values >2 in covariates indicated collinearity.

Second, the relationship between immunocompromise and individual serotypes with >10 isolates was assessed by means of the χ2 or Fisher exact test as required, followed by multinomial regression analysis, using as a reference category the serotype with the odds ratio (OR) closest to 1 for immunocompromise in the univariate analysis. The model was adjusted for age (≤50 or >50 years), toxic habits (smoking and alcohol abuse), nonimmunocompromising comorbidities, and immunocompromise. A second multinomial regression analysis was carried out to explore the association between the assessed serotypes and subcategories of immunocompromised patients, adjusting for covariates. Variables with a P value of <.05 (2-tailed) were considered statistically significant.

RESULTS

Factors Associated With Infection by Groups of Serotypes

A total of 1094 patients were enrolled during the study period, with a mean age of 60.9 (SD, 19.1) years and a mean Charlson score of 2.11 (SD, 2.2). Thirty-six percent of patients (394/1094) fulfilled at least 1 immunocompromise criterion. The infecting serotype was determined for 993 of 1094 patients. The proportion of recovered serotypes that were included in the PCV13 vaccine was 62% (684/993) for the entire 16-year study period and 66% (382/572) for patients enrolled between 2003 and 2011. The coverage of PCV7 was 24.7% for the entire cohort.

Figure 1 shows the proportion between included and nonincluded in PCV13 throughout the study. An increasing proportion of infection due to serotypes not included in PCV13 was observed over the course of the study. Whereas between 2003 and 2009, the proportion of serotypes not included in PCV13 did not exceed 30% of the isolates, in 2010 and 2011 the proportion of non-PCV13 serotypes reached 46% and 53%, respectively, of the overall isolates (P < .05). A simultaneous decrease in the proportion and incidence of PCV7 serotypes was detected in the post-PCV7 period, from 35.4% in the pre-PCV7 period to 18.7% in 2003–2011 (P < .0001; Figure 1). The observed increase in the proportion of infections over time due to serotypes not covered by PCV13 was not associated with an increase in the absolute number of infections by S. pneumoniae strains not covered by PCV13, because the incidence of infection with PCV13 serotypes fell significantly.

Figure 1.

Proportion distribution of 7-valent pneumococcal conjugate vaccine (PCV7), overall 13-valent pneumococcal conjugate vaccine (PCV13), and non-PCV13 serotypes during the 16 years of the study (bars, left axis) and incidence of infection by PCV7, overall PCV13 serotypes, and non-PCV13 serotypes (lines, right axis). *P < .05 for the proportion of non-PCV13 serotypes (2011); **P < .05 for the incidence of PCV13 serotypes (2010–2011). Abbreviations: PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine.

Figure 1.

Proportion distribution of 7-valent pneumococcal conjugate vaccine (PCV7), overall 13-valent pneumococcal conjugate vaccine (PCV13), and non-PCV13 serotypes during the 16 years of the study (bars, left axis) and incidence of infection by PCV7, overall PCV13 serotypes, and non-PCV13 serotypes (lines, right axis). *P < .05 for the proportion of non-PCV13 serotypes (2011); **P < .05 for the incidence of PCV13 serotypes (2010–2011). Abbreviations: PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine.

Table 1 shows the distribution of baseline conditions of the patients, outcome, and penicillin resistance for the serotype isolates analyzed together, according to their inclusion or noninclusion in the PCV13 (overall and PCV7 and non-PCV7 serotypes) and PPV23 formulations. As stated, the non-PCV13/non-PPV23 serotypes were more frequent in elderly individuals previously vaccinated with PPV23, and in patients with comorbidities and immunocompromise. The 6 serotypes present in the PCV13 formulation and not in PCV7 accounted for 44% of isolates as a whole, but only 25% of the recoveries from immunocompromised patients. Table 2 reflects the results of the multivariate analysis after adjusting for immunocompromise, nonimmunocompromising comorbidities, age, and smoking and alcohol abuse. As shown, serotypes not included in PCV13/PPV23 were more frequently isolated in patients with cardiac and respiratory comorbidities, and in certain subgroups of immunocompromised patients (HIV-infected and patients with hematologic cancer). Finally, when the PCV13 serotypes were analyzed by separating PCV7 serotypes from the 6 newly added serotypes in a model with 4 groups, the 6 newly added serotypes were less often found in immunocompromised patients (OR, 0.4; 95% confidence interval [CI], .28–.56).

Table 1.

Underlying Patient Conditions, Resistance to Penicillin, and Outcomes

Characteristic PCV13 (n = 684)
 
PPV23/Non- PCV13 (n = 175) Non-PCV13/Non PPV23 (n = 134) P Value 
Overall PCV13 PCV7 (n = 244) PCV13 and Non-PCV7 (n = 440) 
Age, y, mean (SD) 59.9 (19.1) 59.7 (19.9) 59.9 (18.7) 62.3 (18.51) 65.8 (18.2) <.01 
Toxic habits 
 Smoking 374 (54.6%) 125 (51.2%) 249 (56.5%) 97 (55.4%) 68 (50.7%) ns 
 Alcohol abuse 116 (17%) 40 (16.3%) 76 (17.2%) 30 (17.1%) 23 (17.1%) ns 
Previous PPV23 111 (16.2%) 46 (18.8%) 65 (14.7%) 37 (21.1%) 35 (26.1%) <.05 
Comorbidities 399 (58.3%) 146 (59.8%) 253 (57.5%) 109 (62.3%) 97 (72.4%) <.01 
 Cardiac disease 113 (16.5%) 36 (14.7%) 77 (17.5%) 38 (21.7%) 37 (27.6%) <.01 
  Lung disease 201 (29.3%) 70 (28.6%) 131 (29.7%) 56 (32%) 54 (40.3%) <.05 
 Chronic renal failure 45 (6.5%) 13 (5.3%) 32 (7.2%) 17 (9.7%) 8 (6%) ns 
 Neurological disease 52 (7.6%) 17 (6.9%) 35 (7.9%) 10 (6.8%) 20 (12.3%) ns 
 Liver disease 90 (13.1%) 43 (17.6%) 47 (10.6%) 21 (12.%) 22 (16.4%) ns 
Charlson score, mean (SD) 1.90 (2.13) 2.34 (2.4) 1.66 (1.7) 2.48 (2.5) 2.58 (2.04) <.01 
Immunocompromisea 222 (32.4%) 109 (44.6%) 113 (25.6%) 64 (36.6%) 61 (45.5%) .01 
 HIV infection 83 (12.2%) 55 (22.5%) 28 (6.3%) 27 (15.4%) 21 (15.7%) ns 
 Solid cancer 72 (10.5%) 28 (11.4%) 44 (10%) 24 (13.7%) 19 (14.2%) ns 
 Hematologic cancer 45 (6.7%) 19 (7.7%) 26 (5.9%) 17 (9.7%) 17 (12.7%) <.05 
 Chronic corticosteroid therapy 27 (3.9%) 14 (5.7%) 13 (2.9%) 7 (4%) 10 (7.5%) ns 
 Nonsteroid immunosuppressive therapyb 14 (2%) 5 (2%) 9 (2%) 4 (2.3%) 2 (1.5%) ns 
 Otherc 7 (1%) 2 (1%) 5 (1.1%) ns 
30-day mortality 94 (13.7%) 46 (18.8%) 48 (10.9%) 25 (14.5%) 15 (11.5%) ns 
Penicillin resistanced 60 (8.7%) 55 (22.5%) 5 (1.1%) 0 (0%) 1 (0.8%) <.001 
Characteristic PCV13 (n = 684)
 
PPV23/Non- PCV13 (n = 175) Non-PCV13/Non PPV23 (n = 134) P Value 
Overall PCV13 PCV7 (n = 244) PCV13 and Non-PCV7 (n = 440) 
Age, y, mean (SD) 59.9 (19.1) 59.7 (19.9) 59.9 (18.7) 62.3 (18.51) 65.8 (18.2) <.01 
Toxic habits 
 Smoking 374 (54.6%) 125 (51.2%) 249 (56.5%) 97 (55.4%) 68 (50.7%) ns 
 Alcohol abuse 116 (17%) 40 (16.3%) 76 (17.2%) 30 (17.1%) 23 (17.1%) ns 
Previous PPV23 111 (16.2%) 46 (18.8%) 65 (14.7%) 37 (21.1%) 35 (26.1%) <.05 
Comorbidities 399 (58.3%) 146 (59.8%) 253 (57.5%) 109 (62.3%) 97 (72.4%) <.01 
 Cardiac disease 113 (16.5%) 36 (14.7%) 77 (17.5%) 38 (21.7%) 37 (27.6%) <.01 
  Lung disease 201 (29.3%) 70 (28.6%) 131 (29.7%) 56 (32%) 54 (40.3%) <.05 
 Chronic renal failure 45 (6.5%) 13 (5.3%) 32 (7.2%) 17 (9.7%) 8 (6%) ns 
 Neurological disease 52 (7.6%) 17 (6.9%) 35 (7.9%) 10 (6.8%) 20 (12.3%) ns 
 Liver disease 90 (13.1%) 43 (17.6%) 47 (10.6%) 21 (12.%) 22 (16.4%) ns 
Charlson score, mean (SD) 1.90 (2.13) 2.34 (2.4) 1.66 (1.7) 2.48 (2.5) 2.58 (2.04) <.01 
Immunocompromisea 222 (32.4%) 109 (44.6%) 113 (25.6%) 64 (36.6%) 61 (45.5%) .01 
 HIV infection 83 (12.2%) 55 (22.5%) 28 (6.3%) 27 (15.4%) 21 (15.7%) ns 
 Solid cancer 72 (10.5%) 28 (11.4%) 44 (10%) 24 (13.7%) 19 (14.2%) ns 
 Hematologic cancer 45 (6.7%) 19 (7.7%) 26 (5.9%) 17 (9.7%) 17 (12.7%) <.05 
 Chronic corticosteroid therapy 27 (3.9%) 14 (5.7%) 13 (2.9%) 7 (4%) 10 (7.5%) ns 
 Nonsteroid immunosuppressive therapyb 14 (2%) 5 (2%) 9 (2%) 4 (2.3%) 2 (1.5%) ns 
 Otherc 7 (1%) 2 (1%) 5 (1.1%) ns 
30-day mortality 94 (13.7%) 46 (18.8%) 48 (10.9%) 25 (14.5%) 15 (11.5%) ns 
Penicillin resistanced 60 (8.7%) 55 (22.5%) 5 (1.1%) 0 (0%) 1 (0.8%) <.001 

Data, shown as number (%), are for patients infected by serotypes included in PCV13 (PCV7 and the 6 added serotypes to this formulation); serotypes in PPV23 but not included in PCV13; and serotypes not included in any of the commercial vaccines.

Abbreviations: HIV, human immunodeficiency virus; ns, not significant; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine; SD, standard deviation.

a Fifty-one patients fulfilled >1 condition.

b Includes 16 patients with immunosuppressive therapy for bone marrow or solid organ transplant and 7 patients with autoimmune diseases.

c Includes 7 patients with hypogammaglobulinemia.

d According to Clinical and Laboratory Standards Institute nonmeningeal breakpoints [12].

Table 2.

Multivariate Model (Multinomial Regression Analysis) of the Conditions Associated With Pneumococcal Infection

Condition PCV13 PPV23 and Non-PCV13
 
Non-PPV23/Non-PCV13
 
OR 95% CI OR 95% CI 
Age >50 y Reference category 1.53 .94–2.48 1.88 1.01–3.47 
Tobacco exposure  1.02 .69–1.50 0.66 .42–1.02 
Alcohol exposure  1.03 .63–1.67 1.07 .62–1.85 
Nonimmunocompromising comorbidities  1.06 .72–1.54 1.72 1.11–2.68 
 Cardiac disease  1.29 .82–2.03 1.93 1.19–3.07 
 Lung disease  1.02 .67–2.53 1.57 1.01–2.45 
 Chronic renal failure  1.45 .79–2.68 0.67 .3–1.5 
 Neurological disease  0.97 .51–1.84 1.53 .82–2.86 
 Liver disease  0.81 .46–1.41 1.3 .73–2.31 
Immunocompromise  1.24 .87–1.77 2.01 1.36–2.97 
 HIV infection  2.05 1.14–3.69 2.94 1.46–5.90 
 Solid cancer  1.35 .8–2.28 1.43 .8–2.56 
 Hematologic cancer  1.5 .82–2.74 2.19 1.17–4.07 
 Chronic corticosteroid therapy  0.94 .37–2.22 1.83 .81–4.16 
 Nonsteroid immunocompromising therapy  1.04 .32–3.4 0.42 .08–2.06 
Condition PCV13 PPV23 and Non-PCV13
 
Non-PPV23/Non-PCV13
 
OR 95% CI OR 95% CI 
Age >50 y Reference category 1.53 .94–2.48 1.88 1.01–3.47 
Tobacco exposure  1.02 .69–1.50 0.66 .42–1.02 
Alcohol exposure  1.03 .63–1.67 1.07 .62–1.85 
Nonimmunocompromising comorbidities  1.06 .72–1.54 1.72 1.11–2.68 
 Cardiac disease  1.29 .82–2.03 1.93 1.19–3.07 
 Lung disease  1.02 .67–2.53 1.57 1.01–2.45 
 Chronic renal failure  1.45 .79–2.68 0.67 .3–1.5 
 Neurological disease  0.97 .51–1.84 1.53 .82–2.86 
 Liver disease  0.81 .46–1.41 1.3 .73–2.31 
Immunocompromise  1.24 .87–1.77 2.01 1.36–2.97 
 HIV infection  2.05 1.14–3.69 2.94 1.46–5.90 
 Solid cancer  1.35 .8–2.28 1.43 .8–2.56 
 Hematologic cancer  1.5 .82–2.74 2.19 1.17–4.07 
 Chronic corticosteroid therapy  0.94 .37–2.22 1.83 .81–4.16 
 Nonsteroid immunocompromising therapy  1.04 .32–3.4 0.42 .08–2.06 

In the first model, nonimmunocompromising comorbidities and immunocompromise were analyzed together. In the second model, both conditions were analyzed by subgroup.

Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio; PCV13, 13-valent pneumococcal conjugate vaccine; PPV23, 23-valent pneumococcal polysaccharide vaccine.

Factors Associated With Infection by Individual Serotypes

Figure 2 shows the distribution of individual serotypes and grouped serotypes with >10 isolates in immunocompromised and nonimmunocompromised participants. Figures 3 and 4 reflect the risk of infection by individual serotypes in patients with nonimmunocompromising comorbidities and in immunocompromised patients after adjusting for age, smoking, and alcohol abuse, with serotype 4 as a reference (n = 55 isolates; OR, 1.06 for immunocompromise; Figure 2). As shown, none of the studied serotypes was associated with nonimmunocompromising comorbidities, and serotypes 1 and 7F were less often isolated in this subgroup of patients. Conversely, serotype 1 was less frequently found in immunocompromised patients, whereas serotypes 6A, 11A, 23F, and 33F were independently associated with immunocompromise but without any yearly or geographic clustering that might suggest in-hospital person-to-person transmission (data not shown). Up to 83% of 11A and 72% of 33F isolates, which are not part of the PCV13 formulation, appeared repeatedly in the last 6 years of the study.

Figure 2.

Association between individual isolates and immunocompromise (univariate model) during the 16 years of the study. Abbreviations: CI, confidence interval; OR, odds ratio.

Figure 2.

Association between individual isolates and immunocompromise (univariate model) during the 16 years of the study. Abbreviations: CI, confidence interval; OR, odds ratio.

Figure 3.

Risk of infection (on a logarithmic scale) according to individual serotypes in patients with nonimmunocompromising comorbidities during the 16 years of the study. The model is adjusted for age, smoking, and alcohol abuse. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.

Figure 3.

Risk of infection (on a logarithmic scale) according to individual serotypes in patients with nonimmunocompromising comorbidities during the 16 years of the study. The model is adjusted for age, smoking, and alcohol abuse. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.

Figure 4.

Risk of infection (on a logarithmic scale) by individual serotypes in patients with immunocompromise during the 16 years of the study. The model is adjusted for age, smoking, and alcohol abuse. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.

Figure 4.

Risk of infection (on a logarithmic scale) by individual serotypes in patients with immunocompromise during the 16 years of the study. The model is adjusted for age, smoking, and alcohol abuse. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.

Overall, in the 2003–2011 period, 37.2% (80/215) of the patients with immunocompromise presented infection by serotypes not included in PCV13.

Finally, Table 3 reflects the association between individual serotypes and the underlying condition that predisposed to their isolation in relation to immunocompromise. As shown, in addition to the serotypes with significant relationships with immunocompromised patients overall, serotype 10A was also identified as being independently related to HIV infection.

Table 3.

Associations Between Individual Serotypes With >10 Isolates and Subgroups of Immunocompromised Patientsa

Condition Associated Serotypes OR (95% CI) 
Hematologic cancer 6A 64.47 (10.4–396) 
HIV infection 10A 14.62 (3.06–69.84) 
23F 15.04 (3–75.24) 
Solid tumors 11A 11.16 (2.56–48.65) 
23F 7.09 (1.52–32.94) 
33F 9.55 (2.01–45.39) 
Condition Associated Serotypes OR (95% CI) 
Hematologic cancer 6A 64.47 (10.4–396) 
HIV infection 10A 14.62 (3.06–69.84) 
23F 15.04 (3–75.24) 
Solid tumors 11A 11.16 (2.56–48.65) 
23F 7.09 (1.52–32.94) 
33F 9.55 (2.01–45.39) 

Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio.

a Adjusted for age, smoking, alcohol abuse, and nonimmunocompromising comorbidities.

DISCUSSION

In this study, we identified several patient-related risk factors for acquiring specific pneumococcal serotypes that cause respiratory invasive infection. These associations differ greatly depending on the baseline conditions of the host, especially their immune status. Interestingly, serotypes not covered by the PCV13 and PPV23 formulations were overall more frequently isolated in patients with cardiorespiratory comorbidities and immunocompromise. Although we found no association between nonimmunocompromising comorbidities and individual pneumococcal serotypes, in immunocompromised patients (or some of their subgroups) some serotypes (6A, 10A, 11A, 23F, and 33F) were more frequently isolated. This finding highlights the fact that 3 serotypes (10A, 11A, and 33F) that are not included in the PCV13 formulation are the most frequently isolated in immunocompromised patients even though their prevalence in the whole cohort is low. Serotype 1, conversely, was much more prevalent, but occurred less frequently in the immunocompromised population.

In the literature, individual serotypes are reported to have different clinical manifestations and different outcomes. Some authors [11, 14] described the invasive disease potential of several serotypes and the case-fatality rates for each group. According to their findings, a group of serotypes, including 1, 5, and 7F, identified in the literature as invasive serotypes, rarely cause oropharyngeal colonization but commonly cause bacteremia, showing a low case-fatality rate. A second group of serotypes (3, 6A, 6B, 8, 19F, and 23F) are frequently associated with colonization and rarely cause bacteremia, acting as opportunistic pathogens or microorganisms with low invasive disease potential that cause high severity of illness and mortality [15] . Regarding individual serotypes, serotype 3 was independently associated with septic shock and increased mortality [16], serotypes 1, 3, 7F, and 19A with pneumococcal parapneumonic effusion [17], and serotypes 1 and 3 with empyema [10].

Harboe et al [18] conducted a population-based cohort study of >18 000 patients with invasive pneumococcal disease. Significant differences in mortality were found between different serotypes. In their study, the risk for an adverse outcome between different serotypes changed when the cohort was stratified by low-medium or high comorbidity, according to the Charlson score, suggesting that some baseline conditions may predispose to infection by certain serotypes. The group of serotypes with high invasive disease potential (1, 5, 7F) has been shown to infect mainly young and healthy people [15]. The difficulty of jointly analyzing different serotypes, however, is that individual differences may show wide variation, and few data are available regarding people at risk of infection by individual serotypes. In this respect, Fry et al [19] found that, using serotype 4 as a reference, serotypes 6A, 6B, 9N, 9V, 18C, 19A, 19F, and 23F were more frequently isolated in patients with HIV infection.

Immunocompromised persons are one of the subgroups of special interest when active immunization against S. pneumoniae is considered, because the incidence of invasive pneumococcal disease in these patients can be >20 times higher than in adults without high-risk medical conditions, and only half of the cases of invasive pneumococcal disease among immunocompromised adults in 2010 were caused by serotypes contained in PCV13 [9]. In our study, 63% patients with immunocompromise were infected by serotypes included in PCV13 in the last 9 years, but the incidence of individual serotypes in the subgroups of this cohort differed considerably. Whereas serotype 1 was less frequently found, others (6A, 10A, 11A, 23F, and 33F) were frequently recovered from patients showing immunocompromise. Serotypes not included in the PCV13 and PPV23 formulations were overall more frequent in immunocompromised patients. More specifically, serotypes 10A, 11A, and 33F (not included in PCV13), whose incidence has risen in recent years, were also more frequently isolated in immunocompromised patients.

There seem to be at least 2 reasons for the increased susceptibility of certain population groups: the difference in the persistence rate of individual serotypes in the nasopharynx, and their virulence. With regard to the first point, nearly all the serotypes (6A, 10A, 11A, and 23F) found in immunocompromised patients had a carriage prevalence >5% in previous studies [20], whereas serotypes 1 and 8 had a carriage prevalence around 1%, a difference that may be related to the thickness of the cell wall [20] or to the metabolic demands of the bacterial capsule [21]. With regard to the virulence of the serotypes, in a study of pneumococcal serotypes causing pneumonia and acute exacerbations in patients with COPD, serotypes 10A, 11A, and 33F were more frequently isolated in sputum than in blood samples, suggesting that they are less virulent than 1, 3, 5, and 8, which more frequently caused bacteremia in the same study [22]. Probably, the virulence hypothesis may also explain why serotypes not included in the PPV/PCV formulations were also more frequent in immunocompromised patients, as in this group only serotypes 24F and 23A accounted for >10 isolates. The remaining isolates individually accounted for <1% of the total cohort, suggesting that they rarely cause invasive disease.

Some limitations must be pointed out. First of all, we included only patients from 2 single hospitals in the same geographical area. Therefore, it is unclear whether our results may be extrapolated to other geographic areas. Second, only patients with invasive pneumococcal disease were included; the distribution of serotypes might be different in patients with noninvasive pneumococcal infection, who may present less virulent serotypes. Finally, the study encompassed a 16-year period, and, although host-related factors may be similar, the distribution of serotypes may have changed over this time.

In conclusion, there seem to be specific factors related to immunocompromise that determine the appearance of invasive infection by specific pneumococcal serotypes. These factors are not significantly present in patients with comorbidities but without immunocompromise. Although the coverage of serotypes in PCV13 was high in these patients, some emergent serotypes (10A, 11A, and 33F), which are not included in PCV13, were more prevalent in immunocompromised patients. It seems crucial to monitor the emergence of pneumococcal serotypes that are not included in commercially available vaccines and to assess their association with specific underlying conditions of the host.

Notes

Acknowledgments. We thank Grant Waterer (Perth, Australia) for critical revision of the manuscript.

Financial support. This work was supported in part by the Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Bunyola, Spain (PCI pneumonia).

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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