The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia

G Model

ARTICLE IN PRESS

JVAC 17316 1–6

Vaccine xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Vaccine journal homepage: www.elsevier.com/locate/vaccine

The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia

1

2

3

4 5 6 7 8 9 10 11

Q1

Francisco Sanz Herrero a,∗ , Concepción Gimeno Cardona b,c , Nuria Tormo Palop b , Estrella Fernández Fabrellas a , María Luisa Briones d , Ángela Cervera Juan a , José Blanquer Olivas e a

Pulmonology Department, Consorci Hospital General Universitari de València, 2, Tres cruces av, 46014 València, Spain Microbiology Department, Consorci Hospital General Universitari de València, 2, Tres cruces av, 46014 Valencia, Spain c University of València, Faculty of Medicine, València, 15-17 Blasco Iba˜ nez av, 46010 Valencia, Spain d Pulmonology Department, Hospital Clínic Universitari de València, 17, Blasco Iba˜ nez av, 46010 Valencia, Spain e Intensive Care Unit, Hospital Clínic Universitari de València. 17, Blasco Iba˜ nez av, 46010 Valencia, Spain b

12

13 28

a r t i c l e

i n f o

a b s t r a c t

14 15 16 17 18 19 20

Article history: Received 23 April 2015 Received in revised form 12 December 2015 Accepted 18 January 2016 Available online xxx

21 22 23 24 25 26 27

Keywords: Acute respiratory failure Bacteremia Community-acquired pneumonia Pneumococcal conjugate vaccine Streptococcus pneumoniae

Introduction: Pneumococcal 13-valent vaccine (PCV-13) has a potential role in preventing bacteraemic pneumococcal pneumonia and its complications, but little is known about its ability to specifically prevent respiratory complications. Our aim were to analyse the pneumococcal serotypes associated with the development of respiratory complications and the potential role of PCV-13 in preventing respiratory complications in bacteraemic pneumococcal pneumonia. Material and methods: We analysed demographic characteristics, comorbidities, antibiotic resistances and the outcomes of a cohort of 65 vaccine-naïve bacteraemic pneumococcal pneumonias, stratified by the pneumococcal serotypes included in PCV13 vs. those not included. Complications were clustered as follows: respiratory complications (hypoxemic respiratory failure; mechanical ventilation), systemic complications (septic shock; multiorgan failure), suppurative complications (empyema; pleural effusion; lung abscess). Results: From a population of 65 CAP-SP, 47.7% of the isolates belonged to PCV-13 serotypes group. No differences in comorbidities or clinical manifestations were found between groups. With regard to biochemical parameters, we found more profound hypoxemia levels in PCV-13 serotypes group comparing to non-vaccine group [PaO2 /FiO2 209 (63) vs. 268 (57); p = 0.007]. Global complications were identified in 69.2% (45 patients), and the most frequent were respiratory complications, found in 47.7%. Respiratory complications were detected more frequently in PCV-13 groups compared to non-vaccine groups (61.3% vs. 35.3%; p = 0.036). Overall 30-day mortality was 30.8%. Mortality was similar between both groups (25.8% vs. 35.3%; p = 0.408). Conclusions: Pneumococcal 13-valent conjugate vaccine includes the serotypes which cause more respiratory complications in our series; these serotypes were not associated with higher mortality in our series. PCV-13 may have a potential role in preventing respiratory complications due to bacteraemic pneumonoccal pneumonia. © 2016 Published by Elsevier Ltd.

Abbreviations: CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; CRP, C reactive protein; FEV1/FVC, Forced Expiratory Volume in one second/Forced Vital Capacity; HIV, Human Immunodeficiency Virus; ICU, intensive care unit; IPD, invasive pneumococcal disease; IQR, interquartile range; OR, odds ratio; PaO2 /FiO2 , ratio of partial pressure arterial oxygen and fraction of inspired oxygen; PCV-7, pneumococcal conjugate vaccine 7-valent; PCV-13, pneumococcal conjugate vaccine 13-valent; PPV-23, pneumococcal polysaccharide vaccine 23-Valent; PSI, pneumonia severity index; SD, standard deviation; 95%CI, 95% confidence interval. ∗ Corresponding author. Tel.: +34 963 131 800x437316. E-mail address: sanz [email protected] (F.S. Herrero). http://dx.doi.org/10.1016/j.vaccine.2016.01.038 0264-410X/© 2016 Published by Elsevier Ltd.

Please cite this article in press as: Herrero FS, et al. The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2016.01.038

G Model JVAC 17316 1–6

F.S. Herrero et al. / Vaccine xxx (2015) xxx–xxx

2 29

30Q2 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69

ARTICLE IN PRESS

1. Introduction Bacteraemic pneumococcal pneumonia is a major health problem that makes a clear and deleterious impact on patients’ lives, and presents a challenge to clinicians in the management of its complications [1–4]. Acute respiratory failure is a crucial pathophysiological event in community-acquired pneumonia (CAP) that, per se, is able to define the prognosis [5,6]. Thus the presence of this complication is associated with increased morbidity and mortality, independently of the initial classification of the pneumonia’s severity [7]. The occurrence of complications in pneumonia is determined by the characteristics of the host, but there is also growing evidence that the microorganism itself plays its role in developing certain complications. Thus described, Streptococcus pneumoniae is capable of producing a different phenotypic expression, depending on the capsular serotype. Certain serotypes have been found to be more likely associated specifically with the development of septic shock and death [8–12]. Furthermore, a recent study has reported that infection with serotypes 3, 19A and 19F causes a higher frequency of acute hypoxemic respiratory failure in bacteraemic pneumococcal pneumonia [13]. Currently, the use of 13-valent pneumococcal conjugate vaccine (PCV13) has been shown to decrease the incidence of this disease and to provide effective protection against infection by the serotypes included in it causing invasive pneumococcal disease (IPD), in addition to being a cost-effective measure [14–16]. The vaccine strategies against S. pneumoniae are based on the ecological profile, and the distribution of serotypes that most commonly cause IPD. However, from a clinical point of view, it is important to establish the potential role of PCV13 in preventing the development of the major complications of pneumococcal pneumonia [18–20]. The potential role of PCV13 in preventing hypoxemic respiratory failure in bacteraemic pneumococcal pneumonia has not been explored. We hypothesize that different pneumococcal serotypes included in PCV13 could lead to specific pneumonia outcomes, especially respiratory complications since acute respiratory failure has been described related to infection by serotypes 3, 19A and 19F (included in PCV13). We aim to assess if PCV13 serotypes are associated with worse respiratory outcome in a vaccine-naïve population with bacteraemic pneumococcal pneumonia.

70

2. Materials and methods

71

2.1. Study characteristics/inclusion and exclusion criteria

72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89

This is a retrospective observational study with case analysis of bacteraemic pneumococcal pneumonia requiring hospitalization during the years 2011–2013. The field of study is a tertiary-level 504-bed university hospital (Consorci Hospital General Universitari de València) serving a population of 373,805 inhabitants in Valencia, Spain. The study was approved by the Ethics Committee of the Consorci Hospital General Universitari de València, Reference 05/2007. We included those patients older than 18 years with a diagnosis of community-acquired pneumonia, plus an isolation of S. pneumoniae in blood culture, none of whom had received vaccination against pneumococcus (PCV7, PCV13 or PPV23) during a minimum of the previous 5 years. PPV23 is used for decades, it includes the largest number of serotypes, but does not generate immune memory, antibody levels decrease over the time, and it causes immune tolerance and does not act on nasopharyngeal colonization [21–25]. Pneumonia was defined using at least two or more of the following symptoms: fever, dyspnoea, cough, sputum and chest pain,

together with the appearance of de novo alveolar infiltrates on chest X-rays. Pneumococcal pneumonia aetiology was considered when isolation of S. pneumoniae from blood cultures was obtained. Patients with pneumonia with a record of hospitalization in the previous two weeks were excluded from the analysis, plus those with a diagnosis of probable pneumococcal pneumonia based solely on the results of the urinary antigen. 2.2. Variables analysed Among the variables analysed, the following demographic data were collected: smoking, alcohol consumption (more than 80 g per day) and the use of intravenous drugs. Chronic obstructive pulmonary disease was defined as a history of smoking and the detection of airway obstruction under spirometry (FEV1/FVC < 70), the presence of chronic renal failure, congestive heart failure, and cerebrovascular disease. The following comorbidities were also considered: diabetes mellitus, chronic liver disease (viral, toxic) and history of neoplasia. Immunosuppression was defined as HIV infection, prolonged treatment with corticosteroids (20 mg or more per day of prednisone, or its equivalent, for at least 3 weeks), chemotherapy (either current or in the previous month) and splenectomy. The symptoms and signs analysed included fever, dyspnoea, cough, sputum, chest pain, confusion, respiratory rate and blood pressure. The radiological findings and biochemical data collected at admission included the presence of multilobar radiographic involvement, pleural effusion and the serum urea, C-reactive protein (CRP), leukocyte counts and blood gas values: pH and PaO2 /FiO2 . Data on antibiotic treatments prior to the pneumonia diagnosis and its concordance with the pattern of antibiotic sensitivity, as well as the need for modifications, were analysed. The vaccination status of each patient was obtained from the named computer vaccine register on the Conselleria de Sanitat electronic medical records. 2.3. Assessment of severity The pneumonia severity was determined using the Pneumonia Severity Index score (PSI), based on demographics, comorbidities, physical examination, and laboratory and radiological data at the time of the pneumonia diagnosis [25]. In accordance with 30-day mortality risk, patients were classified as mild (PSI I-III) or severe (PSI V-IV) pneumonia. 2.4. Microbiological diagnosis The diagnosis of pneumococcal bacteraemia required at least one blood culture with the isolation of S. pneumoniae. Thereafter, blood cultures were incubated in the BD BactecTM FX system (Becton Dickinson, Sparks, MD). Antimicrobial susceptibility was studied by E-test® (bioMérieux, Durham, NC) and Clinical and Laboratory Standards Institute (2008) breakpoints were used to investigate penicillin, erythromycin, cefotaxime and levofloxacin susceptibilities [26]. Serotype determination was performed in the laboratory with reference to agglutination of latex particles (Denka Seiken, Tokyo, Japan); some strains were also sent to the National Microbiology Centre for confirmation. 2.5. Streptococcus pneumoniae serotypes S. pneumoniae isolates were classified according to whether serotype was contained in the 13-valent conjugate vaccine

Please cite this article in press as: Herrero FS, et al. The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2016.01.038

90 91 92 93 94 95 96

97

98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123

124

125 126 127 128 129 130

131

132 133 134 135 136 137 138 139 140 141 142

143

144 145

G Model JVAC 17316 1–6

ARTICLE IN PRESS F.S. Herrero et al. / Vaccine xxx (2015) xxx–xxx

(PCV-13 serotypes) including serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F or not (non-PCV-13 serotypes).

14

147

148

2.6. Outcomes

10

151 152 153 154 155 156 157 158

(a) Suppurative complications that group together the parapneumonic pleural effusion, empyema, lung abscess, endocarditis and meningitis; (b) Respiratory complications that include the development of acute respiratory failure defined as a PaO2 /FiO2 < 250, the need for ventilatory support, whether non-invasive or invasive; (c) Systemic complications, defined by the occurrence of acute renal failure, septic shock and multiple organ failure, and (d) The need for ICU admission.

160

Other outcomes as the length of hospital stay and 30-day mortality were also analysed.

161

2.7. Statistical analysis

159

182

The results were expressed as absolute numbers and percentages for categorical variables, and as mean and standard deviation for the continuous ones. The Kolmogorov–Smirnov test was used to assess the sample’s distribution normality. A bivariate analysis was performed to identify those risk factors associated with infection, according to the S. pneumoniae serotype distribution (PCV-13 serotypes vs. non-PCV-13 serotypes). A 2 test (with the Yates correction, as necessary) or the Fisher exact test for categorical variables contrast, were used. Continuous variables were analysed using the Mann–Whitney U test. Multivariate analysis was performed using logistic regression upon the development of respiratory complications as the dependent variable and the group of serotypes as the independent variable, and those variables with p < 0.1, along with those suspected of being related to respiratory complications (COPD, age > 65, bilateral infiltrates on chest X-ray, kidney failure, tobacco use, liver disease, and diabetes mellitus). The results of logistic regression analysis were expressed as an odds ratio (OR) and 95% confidence intervals (95% CI). A value of p < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS v.17.0 statistical software (SPSS Inc. Chicago, IL, USA).

183

3. Results

162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181

193

During the 2011–2013 study period, 75 cases of bacteraemic pneumococcal pneumonia were analysed and 10 of them were excluded due to receipt PCV13 or PPV23 in the past 5 years. From a population of 65 patients, 47.7% (31 cases) belonged to the serogroups included in PCV-13 vaccine, while 52.3% (34 cases) were non-PCV-13 serotypes. Twenty-six different serotypes were isolated, the most frequent of which were vaccine serotypes 3 (38.7%), 7F (16.1%) and 19A (12.9%), while the most frequent non-vaccine serotypes were 11A (20.6%) and 8 and 22F serotypes (11.8%, respectively) (Fig. 1).

194

3.1. Clinical characteristics

184 185 186 187 188 189 190 191 192

195 196 197 198 199 200

Age values were normally distributed (Z = 0.911, p = 0.378) and the mean age was 60.5 (SD 20.5) years, and 62.2% were male. 81.5% of patients (53 cases) had some type of comorbidity, the most frequent being some factor of immunosuppression (40%), smoking habit (36.9%) and diabetes mellitus (21.5%). Univariate analysis showed that the demographics and distribution of comorbidities

8 6 4 2 0

PCV-13 serotypes

6C 7A 8A 9L 9N 10A 11A 15A 15B 15C 17 21 22F 24B/F 31 34

150

The occurrences of the following complications were assessed:

1 3 6B 7F 9V 14 19A 19F 23F

149

12

Frequency

146

3

Non-PCV-13 serotypes

Fig. 1. Distribution of serotypes. In white: vaccine serotypes PCV13 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F). In grey: non-vaccine serotypes

were similar between the two groups (Table 1). The clinical manifestations indicated that patients infected with pneumococci of vaccine serotypes had significantly higher frequency of dyspnoea (Table 1). The distribution for PaO2 /FiO2 was normal (Z = 0.909, p = 0.381), significantly, patients infected with vaccine serotypes showed worse hypoxemia with lower levels of PaO2 /FiO2 than those infected with non-vaccine serotypes [209 (SD 63) vs. 268 (SD 57); p = 0.007] (Fig. 2). No other differences between radiological findings and laboratory data were found. Patterns of antibiotic treatment did not differ between groups (Table 1). 3.2. Antibiotic resistances Some kind of antibiotic resistance was detected in 38.5% of the isolates, primarily erythromycin (35.4%, 23 cases), however, no statistical differences between isolates belonging to the vaccine serotypes and non-vaccine ones were observed (Table 2). 3.3. Outcomes 45 patients (69.2%) presented some type of complication, the most frequent were respiratory complications (47.7%, 31 cases) in which 31 patients developed respiratory complications (21 PaO2 /FiO2 < 250 and 7 of them needed invasive mechanical ventilation and 10 patients needed non-invasive mechanical ventilation in which PaO2 /FiO2 were >250 and <300) and systemic ones (44.6%, 29 cases). Patients infected with vaccine serotypes pneumococci showed significantly more respiratory complications when comparing with non-vaccine serotypes group (61.3% vs. 35.3%; p = 0.036) (Table 3). The overall 30-day mortality was 30.8% (20 patients), although no statistically significant differences between groups were observed (35.3% vs. 25.8%; p = 0.408) (Table 3). The regression logistic model included as dependent variable respiratory complications and the following independent variables: PCV-13 serotypes, dyspnoea, leucocytes count less than 5.000/ml, age >65, COPD, bilateral infiltrates on chest X-ray, kidney failure, tobacco use, liver disease, and diabetes mellitus. Multivariate analysis confirmed that infection by PCV-13 serotypes was independently associated with a greater development of respiratory complications: OR 4.67 (95% CI 1.35–16.04); p = 0.015. 4. Discussion The main finding of our study was the different outcome of bacteraemic pneumococcal pneumonia depending on pneumococcal serotype. An increased detection of respiratory complications from the serotypes integrated in the 13-valent conjugate vaccine

Please cite this article in press as: Herrero FS, et al. The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2016.01.038

201 202 203 204 205 206 207 208 209 210

211

212 213 214 215

216

217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236

237

238 239 240 241

G Model

ARTICLE IN PRESS

JVAC 17316 1–6

F.S. Herrero et al. / Vaccine xxx (2015) xxx–xxx

4

Table 1 Demographic data, comorbidities, clinical manifestations, complementary tests and treatment. Non-PCV-13 serotypes (n = 34; 52.3%)

Non-adjusted OR (95%CI)

p

63.2 (18) 14 (45.2) 8 (25.8)

– 0.82 (0.31–2.19) 0.49 (0.17–1.43)

0.323 0.696 0.191

28 (82.4) 16 (47.1) 2 (5.9) 6 (17.6) 12 (35.3) 8 (23.5) 3 (8.8) 11 (32.4) 16 (47.1) 5 (14.7) 6 (17.6) 5 (14.7) 2 (5.9)

25 (80.6) 8 (25.8) 6 (19.4) 5 (16.1) 6 (19.4) 5 (16.1) 2 (6.5) 4 (12.9) 10 (32.3) 3 (9.7) 5 (16.1) 9 (29) 6 (19.4)

0.89 (0.26–3.13) 0.39 (0.14–1.12) 3.84 (0.71–20.68) 0.90 (0.24–3.30) 0.44 (0.14–1.37) 0.62 (0.18–2.17) 0.71 (0.11–4.58) 0.31 (0.09–1.11) 0.54 (0.19–1.48) 0.62 (0.14–2.85) 0.89 (0.24–3.29) 2.37 (0.70–8.08) 3.84 (0.71–20.68)

0.859 0.076 0.099 0.870 0.151 0.456 0.720 0.063 0.224 0.538 0.870 0.161 0.099

3.4 (2.6) 26 (76.5) 12 (35.3) 20 (58.8) 14 (41.2) 9 (26.5) 3 (8.8) 7 (20.6) 17 (50) 7 (20.6) 25 (75.3) 10.6 (10)

2.9 (3) 27 (87.1) 20 (64.5) 20 (64.5) 12 (38.7) 11 (35.5) 2 (6.5) 9 (29) 14 (45.2) 6 (19.4) 24 (77.4) 10.9 (7)

– 2.08 (0.56–7.74) 3.33 (1.21–9.23) 1.27 (0.47–3.47) 0.90 (0.33–2.44) 1.53 (0.53–4.41) 0.71 (0.11–4.58) 1.58 (0.51–4.92) 0.82 (0.31–2.19) 0.93 (0.27–3.13) 1.23 (0.39–3.84) –

0.679 0.270 0.019 0.638 0.839 0.432 0.720 0.430 0.696 0.901 0.716 0.169

Complementary tests Multilobar X-ray Pleural effusion Leucocytes < 5000 Urea > 7 mmol/L pH< 7.35 PaO2 /FiO2 PaO2 /FiO2 < 250 CRP (mg/dl)

7 (20.6) 5 (14.7) 10 (29.4) 27 (81.8) 4 (22) 268 (57) 9 (24.5) 22.6 (14.6)

9 (29) 5 (16.1) 2 (6.5) 21 (67.7) 6 (37.5) 209 (63) 12 (37.7) 26.2 (17.6)

1.58 (0.51–4.92) 1.12 (0.29–4.29) 0.16 (0.03–0.83) 0.47 (0.15–1.49) 2.10 (0.47–9.44) – 3.0 (0.70–12.92) –

0.430 0.874 0.017 0.194 0.329 0.007 0.134 0.378

Antibiotic treatment Previous antibiotic Antibiotic concordance Antibiotic change

4 (11.8) 32 (94.1) 11 (33.3)

2 (6.5) 31 (100) 7 (22.6)

0.52 (0.09–3.04) 0.51 (0.39–0.65) 0.58 (0.19–1.77)

0.460 0.170 0.339

Demographic data Age Age > 65 years Women

58.1 (22.5) 17 (50) 14 (41.2)

Comorbidities Some comorbidity Current smoker Alcoholism COPD Previous pneumonia Neoplasia Hematological Neoplasia HIV infection Immunodepression Kidney failure Chronic liver disease Diabetes mellitus Cerebrovascular disease Clinical manifestations Evolution in days Fever Dyspnoea Coughing Sputum production Chest pain Arthromyalgia Confusion RR > 30 rpm SBP < 90 mmHg PSI IV-V Length of stay (survivors)

PCV-13 serotypes (n = 31; 47.7%)

COPD: chronic obstructive pulmonary disease. CRP: C reactive protein. PaO2 /FiO2 : ratio of partial pressure arterial oxygen and fraction of inspired oxygen. PSI: pneumonia severity index. PCV: pneumococcal conjugate vaccine. RR: respiratory rate. SBP: systolic blood pressure.

Fig. 2. PaO2 /FiO2 values (mean and SD) in different groups of serotypes (p = 0.007).

was observed in our series. Moreover, it was also noted that more than half the bacteraemic pneumococcal pneumonia cases in our area of work were caused by serotypes not included in the PCV-13. When confronted with the infection, the clinical expression is configured by the host’s susceptibility and response to it, and determined by the causative microorganism. Thus, infection by different S. pneumoniae serotypes may confer a range of different clinical expression. In two groups of paediatric pneumococcal serotypes, Brueggeman et al. described them as high potential (serotypes 1, 5, 7F) or low potential for invasiveness (3, 6A, 6B, 8, 19F, 23F) with the consequent prognostic correlation [27]. It has been reported that the association between infection with certain serotypes and mortality remains constant in different studies, from a variety of geographical areas where the most lethal serotypes identified were 3, 6A, 6B, 9N, 11A, 16F, 19A and 19F [8–11]. The phenotypic profile in the development of complications appears to be defined by the serotype causing infection. Thus, the presence of septic shock is associated with infection by serotype 3 and 19A [10,12,28,29]. However, there has been little study focused

Please cite this article in press as: Herrero FS, et al. The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2016.01.038

242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262

G Model

ARTICLE IN PRESS

JVAC 17316 1–6

F.S. Herrero et al. / Vaccine xxx (2015) xxx–xxx

5

Table 2 Antibiotic sensitivity.

Sensitivity to penicillin Sensitivity to erythromycin Sensitivity to cefotaxime Sensitivity to levofloxacin

Non-PCV-13 serotypes (n = 34; 52.3%)

PCV-13 serotypes (n = 31; 47.7%)

Non-adjusted OR (95%CI)

p

34 (100) 25 (73.5) 34 (100) 33 (97.1)

28 (90.3) 17 (54.8) 29 (93.5) 28 (90.3)

0.45 (0.34–0.59) 2.29 (0.81–6.47) 0.46 (0.35–0.60) 0.52 (0.09–3.04)

0.063 0.115 0.132 0.460

Non-PCV-13 serotypes (n = 34; 52.3%)

PCV-13 serotypes (n = 31; 47.7%)

Non-adjusted OR (95%CI)

p

20 (58.8) 6 (17.6) 12 (35.3) 15 (44.1) 5 (14.7) 7 (20.6) 12 (35.3)

25 (80.6) 5 (16.1) 19 (61.3) 14 (45.2) 4 (12.9) 4 (12.9) 8 (25.8)

2.92 (0.95–8.96) 0.89 (0.24–3.29) 2.90 (1.06–7.96) 1.04 (0.39–2.78) 0.86 (0.21–3.54) 0.57 (0.15–2.18) 0.58 (0.19–1.77)

0.057 0.870 0.036 0.933 0.834 0.409 0.408

Table 3 Outcomes. Complications and mortality.

Overall complications Supurative complications Respiratory complications Systemic complications Septic shock ICU admission 30-Day mortality

263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308

specifically in the occurrence of complications related to the target organ involvement in pneumonia. In this sense, it has been found that suppurative complications (empyema, pleural effusion or necrotizing pneumonia) occur most frequently in the presence of a pneumococcal infection with capsular serotypes 1, 3, 5, 7F, 8 and 19A [10,30,31]). Nevertheless, recent work that evaluated clinical characteristics and pulmonary complications, which were defined as pleural effusion, empyema or multilobar involvement, and pneumococcal pneumonia, reported a lack of correlation between serotype causing infection and the development of the aforesaid complications, although only pneumococcal serotypes were identified in 13.4% of cases [32]. In our series, a greater presence of respiratory failure and respiratory complications were found in the patient group infected by serotypes included in the 13-valent conjugate vaccine, represented mainly by serotypes 3, 7F and 19A. These figures are consistent with the work of Burgos et al. which described how serotypes 3, 19A and 19F were independently associated with the development of hypoxemic respiratory failure, multilobar involvement and the need for mechanical ventilation [13]. The fact that certain serotypes are related to the specific development of respiratory failure does not have a well-defined patho-physiological explanation. It has been hypothesised that the features of the polysaccharide capsule of pneumococcus (eg: its thickness), determine a higher resistance to the action of neutrophils in the lungs and, therefore, a greater persistence of the microorganism there, consequently causing a prolonged and greater immune response and lung injury, as is characteristic of serotypes 3, 19F and 19A [9,10,13,31]. Moreover, different serotypes differ in their ability to adhere to the respiratory epithelium according to the adhesions they express, resulting in a variation in the virulence of the serotype dependent strain [13,33]. It is possible; therefore, that the ability to adhere to the respiratory epithelium, and the resistance to phagocytosis, cause a decrease in bacterial clearance, which could, in that case, produce a greater inflammatory response locally, leading to acute lung injury and thus an oxygenation alteration due to the shunt effect. The results of our study have potential practical application, given that, with the use of PCV-13, invasive pneumococcal disease could be prevented efficiently due to the fact that the major serotypes causing respiratory complications are included in the vaccine, which are the source of significant morbidity, as well as a risk factor for mortality [5,34,35]. Our work has some limitations that should be considered: this study is not designed as a work of epidemiological surveillance, so the results could not be broadly generalized. Due to the

retrospective characteristic of our study an inherent selection bias could not be excluded. On the other hand, Microbiology laboratory provided information of all pneumococcal isolated in blood cultures causing pneumonia during the study period, and clinical data were recorded. A possible limitation could be a different distribution of certain comorbidities (for example COPD) between groups that could be associated with acute hypoxemic respiratory failure but we did not find differences statistically significant comparing comorbidities between vaccine and non-vaccine serotypes groups. Although in our community the overall rates of PCV-7 vaccination and PPV-23 in the general population are not known, nor the influence of the dynamics of serotypes, it was, nevertheless, possible to document our patients’ vaccination status by reviewing the current and reliable vaccination records provided by Valencian Community Public Health System. PPV23 was first introduced in Spain in 1999, PVC7 was introduced in 2000 and PCV13 was first introduced in 2010. PCV13 was recommended in 2011 for adults older than 50 years and for people from 19 to 50 in 2013 [36]. The PPV23 vaccination uptake in adult population (>60 years) in Spain ranges from 52.5% to 66% [37,38]. Data from a recent Spanish study has demonstrated that the incidence and the pattern of serotypes causing invasive pneumococcal disease has changed following the use of PCV7 and PCV13, mainly in children population and moderately in adults. However this potential serotypes replacement and herd immunity had no impact the distribution of clinical presentation or in the disease severity in Spain [39]. Moreover, despite the high mortality in our series, we found no association between mortality and the different serotypes perhaps attributable to a possible beta error. The sample size of our study could be a potential limitation but it represents the number of patients with bacteraemic pneumococcal pneumonia in our geographic area between 2011 and 2013. Due to the characteristics of our study (retrospective, single centre) further studies with prospective and multicentre design are needed to confirm our results. We conclude that the PCV13 serotypes are specifically associated with the development of respiratory complications. We believe that our data provide evidence for a potential preventive role of respiratory complications in bacteraemic pneumococcal pneumonia through the use of PCV13 but further studies are needed to confirm these findings.

Uncited reference [17].

Please cite this article in press as: Herrero FS, et al. The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2016.01.038

309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349

Q3

350

G Model JVAC 17316 1–6

F.S. Herrero et al. / Vaccine xxx (2015) xxx–xxx

6 351

352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367

368

369

370

371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421

ARTICLE IN PRESS

Author contributions Dr. Sanz, Dr. Gimeno, Dr. Fernández-Fabrellas and Dr. Blanquer are the guarantor of the content of this manuscript, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Sanz, Dr. Gimeno and Dr. Blanquer contributed to the study conception and design, acquisition of data, data analysis and interpretation, critical review of the manuscript, and approval of the final version to be published. Dr. Sanz, Dr. Gimeno, Dr. Fernández-Fabrellas, Dr. Tormo and Dr. Blanquer contributed to the data analysis, critical review of the manuscript, and approval of the final version to be published. Dr. Briones contributed to the acquisition of data, data analysis and interpretation, critical review of the manuscript, and approval of the final version to be published. Dr. Cervera contributed to the acquisition of data, data analysis and interpretation, critical review of the manuscript, and approval of the final version to be published. Conflict of interest statement The authors declare that they have no competing interests. References [1] Said MA, Johnson HL, Nonyane BA, Deloria-Knoll M, O’Brien KL, AGEDD Adult Pneumococcal Burden Study Team, et al. Estimating the burden of pneumococcal pneumonia among adults: a systematic review and metaanalysis of diagnostic techniques. PLOS ONE 2013;8:e60273, http://dx.doi.org/ 10.1371/journal.pone.0060273. [2] Kalin M, Ortqvist A, Almela M, Aufwerber E, Dwyer R, Henriques B, et al. Prospective study of prognostic factors in community-acquired bacteraemic pneumococcal disease in 5 countries. J Infect Dis 2000;182:840–7. [3] Lynch 3rd JP, Zhanel GG. Streptococcus pneumoniae: epidemiology, risk factors, and strategies for prevention. Semin Respir Crit Care Med 2009;30: 189–209. [4] Lim WS, Macfarlane JT, Boswell TC, Harrison TG, Rose D, Leinonen M, et al. Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines. Thorax 2001;56: 296–301. [5] Rosón B, Carratalà J, Dorca J, Casanova A, Manresa F, Gudiol F. Etiology, reasons for hospitalization, risk classes, and outcomes of community-acquired pneumonia in patients hospitalized on the basis of conventional admission criteria. Clin Infect Dis 2001;33(2):158–65. [6] Majumdar SR, Eurich DT, Gamble JM, Senthilselvan A, Marrie TJ. Oxygen saturations less than 92% are associated with major adverse events in outpatients with pneumonia: a population-based cohort study. Clin Infect Dis 2011;52(3):325–31. [7] Sanz F, Restrepo MI, Fernández E, Briones ML, Blanquer R, Mortensen EM, et al. Is it possible to predict which patients with mild pneumonias will develop hypoxemia? Respir Med 2009;103:1871–7. [8] Martens P, Worm SW, Lundgren B, Konradsen HB, Benfield T. Serotype-specific mortality from invasive Streptococcus pneumoniae disease revisited. BMC Infect Dis 2004;4(June):21. [9] Weinberger DM, Harboe ZB, Sanders EA, Ndiritu M, Klugman KP, Rückinger S, et al. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis 2010;51(6):692–9. [10] Grabenstein JD, Musey LK. Differences in serious clinical outcomes of infection caused by specific pneumococcal serotypes among adults. Vaccine 2014;32(21):2399–405. [11] Luján M, Gallego M, Belmonte Y, Fontanals D, Vallès J, Lisboa T, et al. Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia. Eur Respir J 2010;36(5):1073–9. ˜ [12] Garcia-Vidal C, Ardanuy C, Tubau F, Viasus D, Dorca J, Linares J, et al. Pneumococcal pneumonia presenting with septic shock: host- and pathogen-related factors and outcomes. Thorax 2010;65(1):77–81. [13] Burgos J, Luján M, Larrosa MN, Fontanals D, Bermudo G, Planes AM, et al. Risk factors for respiratory failure in pneumococcal pneumonia: the importance of pneumococcal serotypes. Eur Respir J 2014;43(2):545–53. [14] Bonten MJ, Huijts SM, Bolkenbaas M, Webber C, Patterson S, Gault S, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med 2015;372(12):1114–25. [15] Tomczyk S, Bennett NM, Stoecker C, Gierke R, Moore MR, Whitney CG, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014;63:822–5.

[16] von Gottberg A, de Gouveia L, Tempia S, Quan V, Meiring S, von Mollendorf C, et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N Engl J Med 2014;371:1889–99. [17] Strutton DR, Farkouh RA, Earnshaw SR, Hwang S, Theidel U, Kontodimas S, et al. Cost-effectiveness of 13-valent pneumococcal conjugate vaccine: Germany, Greece, and The Netherlands. J Infect 2012;64:54–67. [18] Navarro Torné A, Dias JG, Quinten C, Hruba F, Busana MC, Lopalco PL, et al. European enhanced surveillance of invasive pneumococcal disease in 2010: data from 26 European countries in the post-heptavalent conjugate vaccine era. Vaccine 2014;32:3644–50. ˜ C, Ciruela P, Esteva C, Marco F, Navarro M, Bartolome R, et al. [19] Munoz-Almagro Serotypes and clones causing invasive pneumococcal disease before the use of new conjugate vaccines in Catalonia, Spain. J Infect 2011;63:151–62. [20] Isaacman DJ, McIntosh ED, Reinert RR. Burden of invasive pneumococcal disease and serotype distribution among Streptococcus pneumoniae isolates in young children in Europe: impact of the 7-valent pneumococcal conjugate vaccine and considerations for future conjugate vaccines. Int J Infect Dis 2010;14:e197–209, http://dx.doi.org/10.1016/j.ijid.2009.05.010. [21] Andrews NJ, Waight PA, George RC, Slack MP, Miller E. Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales. Vaccine 2012;30:6802–8. [22] Shapiro ED, Berg AT, Austrian R, Schroeder D, Parcells V, Margolis A, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991;325:1453–60. [23] Poolman J, Borrow R. Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines. Expert Rev Vacc 2011;10:307–22. [24] Russell FM, Carapetis JR, Balloch A, Licciardi PV, Jenney AW, Tikoduadua L, et al. Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial. Vaccine 2010;28:3341–9. [25] Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;3364:243–50. [26] Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: 18th informational supplement. CLSI document M100-S18. Wayne, PA: Clinical and Laboratory Standards Institute; 2008. [27] Brueggemann AB, Griffiths DT, Meats E, Peto T, Crook DW, Spratt BG. Clonal relationships between invasive and carriage Streptococcus pneumoniae and serotype- and clone-specific differences in invasive disease potential. J Infect Dis 2003;187(9):1424–32. [28] Burgos J, Falcó V, Borrego A, Sordé R, Larrosa MN, Martinez X, et al. Impact of the emergence of non-vaccine pneumococcal serotypes on the clinical presentation and outcome of adults with invasive pneumococcal pneumonia. Clin Microbiol Infect 2013;19(4):385–91. [29] Ahl J, Littorin N, Forsgren A, Odenholt I, Resman F, Riesbeck K. High incidence of septic shock caused by Streptococcus pneumoniae serotype 3-a retrospective epidemiological study. BMC Infect Dis 2013;13:492. [30] Song JY, Nahm MH, Moseley MA. Clinical implications of pneumococcal serotypes: invasive disease potential, clinical presentations, and antibiotic resistance. Korean Med Sci 2013;28(1):4–15. [31] Burgos J, Lujan M, Falcó V, Sánchez A, Puig M, Borrego A, et al. The spectrum of pneumococcal empyema in adults in the early 21st century. Clin Infect Dis 2011;53(3):254–61. ˜ [32] Cillóniz C, Ewig S, Polverino E, Munoz-Almagro C, Marco F, Gabarrús A, et al. Pulmonary complications of pneumococcal community-acquired pneumonia: incidence, predictors, and outcomes. Clin Microbiol Infect 2012;18(11):1134–42. [33] Sanchez CJ, Hinojosa CA, Shivshankar P, Hyams C, Camberlein E, Brown JS, et al. Changes in capsular serotype alter the surface exposure of pneumococcal adhesins and impact virulence. PLoS ONE 2011;6(10):e26587, http://dx.doi.org/10.1371/journal.pone.0026587. [34] Bewick T, Greenwood S, Lim WS. What is the role of pulse oximetry in the assessment of patients with community-acquired pneumonia in primary care? Prim Care Respir J 2010;19(4):378–82. [35] Buising KL, Thursky KA, Black JF, MacGregor L, Street AC, Kennedy MP, et al. Identifying severe community-acquired pneumonia in the emergency department: a simple clinical prediction tool. Emerg Med Australas 2007;19(5):418–26. [36] Picazo JJ, González-Romo F, García Rojas A, Peréz-Trallero E, Gil Gregorio P, de la Cámara R, et al. Consenso sobre la vacunación anti-neumocócica en el adulto con patología de base. Rev Esp Quimioter 2013;26:232–52. [37] Gutierrez Rodriguez MA, Ordobas Gavin MA, Garcia-Comas L, Sanz Moreno JC, Cordoba Deorador E, Lasheras Carbajo MD, et al. Effectiveness of 23-valent pneumococcal polysaccharide vaccine in adults aged 60 years and over in the Region of Madrid, Spain, 2008–2011. Euro Surveill 2014;19(40), pii=20922. [38] Pradas R, Gil de Miguel A, Álvaro A, Gil-Prieto R, Lorente R, Méndez C, et al. Budget impact analysis of a pneumococcal vaccination programme in the 65-year-old Spanish cohort using a dynamic model. BMC Infect Dis 2013;13(April):175, http://dx.doi.org/10.1186/1471-2334-13-175. [39] Guevara M, Ezpeleta C, Gil-Setas A, Torroba L, Beristain X, Aguinaga A, et al. Reduced incidence of invasive pneumococcal disease after introduction of the 13-valent conjugate vaccine in Navarre, Spain, 2001–2013. Vaccine 2014;32(22):2553–62.

Please cite this article in press as: Herrero FS, et al. The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2016.01.038

422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505