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ev Clin Esp. 2013;213(1):8---15

Revista ClínicaEspañola

www.elsevier.es/rce

RIGINAL ARTICLE

neumococcal infections in oncohematological patients after thentroduction of conjugate vaccine�

. Pérez de la Blanca-Burgosa,∗, A. Villoslada-Gelaberta, M. Garau-Colomb,. González-Michelouda, M.C. Gallegos-Álvarezb, A. Payeras-Cifrea

Servicio de Medicina Interna, Hospital Son Llátzer, Palma de Mallorca, SpainServicio de Microbiología, Hospital Son Llátzer, Palma de Mallorca, Spain

eceived 9 February 2012; accepted 6 June 2012vailable online 17 November 2012

KEYWORDSStreptococcuspneumoniae;Cancer;Conjugate vaccine;Pneumococcal;Oncology illness

AbstractObjectives: To know the symptoms and predominant serotypes of pneumococcal infection inpatients with oncohematological illness after introduction of 7-valent pneumococcal conjugatevaccine.Patients and methods: A prospective study (January 2006---May 2011) was made for all theincident cases of infection in oncohematological patients over 17 years of age in whom Strep-tococcus pneumoniae was isolated.Results: A total of 131 episodes of incident cases of pneumococcal infection in 122 patients(median age of 67 years) were detected. Of these, 50% were related to health/nosocomialcare (p < .001), 39.7% to pneumonias and 45.1% to lower respiratory tract infections, withoutradiological condensation. In comparison of the 803 incident cases of pneumococcal infectionduring the same period with patients without oncohematological disease, the oncohematolog-ical patients were more frequently males (p < .001), who had pneumonia episodes with higherFINE scores (p < .001), lower risk of death non-directly associated with pneumococcal infection(p = .006) and showed reduced susceptibility to levofloxacin (p = .043). Non-vaccine serotypespredominated.Conclusions: Pneumococcal infections in oncohematological patients are more frequent in

males, mainly with lung neoplasms. They are heath care related, but not related to chemother-apy or neutropenia. After the introduction of heptavalent conjugate vaccines in pediatrics, thenon-vaccine serotypes predominate.© 2012 Elsevier Espana, S.L. All rights reserved.

� Please cite this article as: Pérez de la Blanca-Burgos M, et al. Infección neumocócica en pacientes oncohematológicos tras la introduccióne la vacuna conjugada. Rev Clin Esp. 2013;213:8---15.∗ Corresponding author.

E-mail address: mariaperezdela@hotmail.com (M. Pérez de la Blanca-Burgos).

254-8874/$ – see front matter © 2012 Elsevier Espana, S.L. All rights reserved.

Pneumococcal infections in oncohematological patients 9

PALABRAS CLAVEStreptococcuspneumoniae;Cáncer;Vacuna conjugada;Neumococo;Enfermedadoncológica

Infección neumocócica en pacientes oncohematológicos tras la introducción de lavacuna conjugada

ResumenObjetivo: Precisar la clínica y los serotipos predominantes en las infecciones neumocócicasincidentes en pacientes oncohematológicos tras la introducción de la vacuna conjugada hep-tavalente.Pacientes y métodos: Serie de casos prospectiva (enero 2006- mayo 2011) de la totalidad decasos de infección, incidentes en pacientes oncohematológicos de más de 17 anos de edad, enlos que se aisló Streptococcus pneumoniae.Resultados: Se detectaron 131 episodios de infección neumocócica, incidentes en 122 pacientes(mediana de edad: 67 anos). El 50% se relacionó con atención sanitaria/nosocomial. El 39,7%fueron neumonías y el 45,1% infecciones del tracto respiratorio bajo sin condensación radiológ-ica. Con respecto a los 803 casos de infección neumocócica, incidentes durante el mismo periodoen pacientes sin enfermedad oncohematológica, los pacientes oncohematológicos fueron másfrecuentemente varones (p < 0,001), presentaron neumonías con índices de FINE más altos(p < 0,001), una mortalidad no atribuible a la infección menor (p < 0,006) y una mayor prob-abilidad de sensibilidad disminuida a levofloxacino (p = 0,043). Predominaron los serotipos novacunales.Conclusiones: Las infecciones neumocócicas incidentes en pacientes oncohematológicos se pre-sentan predominantemente en varones, afectos de cánceres de pulmón. Se relacionan conla atención sanitaria, pero no con exposición reciente a quimioterapia o neutropenia. Trasla introducción de la vacuna pediátrica heptavalente conjugada predominan los serotipos novacunales.© 2012 Elsevier Espana, S.L. Todos los derechos reservados.

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Introduction

Streptococcus pneumoniae (S. pneumoniae) is one of themain causes of morbidity and mortality worldwide. TheWorld Health Organization estimates that approximately 1million children die from pneumococcal disease each year,the majority of whom live in developing countries.1 S. pneu-moniae is also the primary cause of community-acquiredbacterial pneumonia, accounting for 40% of hospital admis-sions in adults.2,3 Currently, administration of the 23-valentpneumococcal polysaccharide vaccine is recommended. Thisvaccine includes the 23 serotypes that cause 90% of severeinfections in patients over 65 years of age and in thoseaffected with chronic diseases or receiving immunosuppres-sion. In 2000, the US approved the pediatric heptavalentconjugate vaccine (VCN-7), which consists of conjugatedpolysaccharides of 7 of the more than 90 known serotypesof S. pneumoniae (4, 6B, 9V, 14, 18C, 19F and 23F). Its usein Spain has been authorized since June 2001. The routinevaccination with VCN-7 caused a direct reduction in the inci-dence of invasive pneumococcal disease in children, and anindirect reduction in adults, and also lowered the rates ofpneumonia and otitis.4---9 In addition, the vaccination withVCN-7 had consequences on the state of the nasopharyngealcarrier, replacing the serotypes included in the vaccine withother serotypes, and also impacted the strains that cause thedisease.7,10,11 Moreover, data have been published suggestingchanges in the clinical presentation and severity of the inva-

sive pneumococcal disease, with more frequent infectionsin younger individuals and a higher rate of complicationssuch as empyema.7,12,13 A number of clinical conditions andimmunosuppression states are known to be risk factors for

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neumococcal infection in children and adults.14,15 Simi-ar epidemiological changes as those described after thentroduction of the VCN-7 have also been observed in somemmunosuppressed patient groups, such as those infectedy HIV and at-risk patients, as is the case for those affectedy sickle cell anemia.5,13,15---17 Patients with oncohematologiconditions constitute a high-risk group for pneumococcalnfection.15,16,18 Few studies have been conducted on theonsequences of the pediatric VCN-7 vaccination in this pop-lation group.5,16

This study was aimed at understanding the clinicalharacteristics of pneumococcal infection in patients withncident oncohematologic disease in our community afterhe introduction of the VCN-7 in pediatrics. The study objec-ives also included describing the predominant serotypesnd their antimicrobial susceptibility.

atients and methods

his is a prospective series of cases that included all episodesf incident pneumococcal infection in patients with onco-ematologic disease treated from January 2006 to May 2011post-vaccine period), in both the hospital inpatient settingnd the outpatient center of our institution. Our center pro-ides care for a population of 220,000 inhabitants and hasncology and hematology departments that share a hospitalnit and an outpatient center.

All episodes of pneumococcal infection were included,hich were defined as the isolation of S. pneumoniae inny sample from patients over 17 years of age with a his-ory of active or inactive oncohematologic disease. The data

10

What we know

Since the authorization to use the heptavalent pneumo-coccal conjugate vaccine in children, there has been areduction in the incidence of invasive pneumococcaldisease in various patient populations in both childrenand adults. There has also been a reduction in the ratesof pneumonia and otitis and in the infections caused bythe serotypes included in the vaccine. However, fewdata are available on oncohematological patients.

What this article provides

The incident pneumococcal infection in the oncohema-tological patients included in this study predominantlyaffected males, especially as a lower respiratory tractinfection. These were frequently nosocomial infec-tions, i.e., related to the healthcare provided. Theywere not related to the administration of chemother-apy or neutropenia and did not show a greater rateof complications or mortality. The prevalent serotypes

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were different from those included in the vaccine.The Editors

ere extracted from a database of pneumococcal infec-ion that has been jointly and prospectively compiled sinceanuary 2006 by the Microbiology and Internal Medicineepartments. We excluded episodes with positive isolatesonsidered to be colonizations with no attributable symp-oms.

A neoplasm was considered active if it met any of the fol-owing criteria: (a) new diagnosis or recurrence of a previouseoplasm during hospitalization for pneumococcal infec-ion; (b) surgery, chemotherapy and/or radiation therapy inhe 6 months prior to infection; and (c) untreated neoplasmue to patient refusal or as a result of palliative treatmentt the physician’s discretion.

The following variables were collected from all patientsn the study:

-- Demographics: gender and age.-- Origin of the infection: (1) community: if there was no

previous contact with the healthcare setting; (2) associ-ated with healthcare: as long as any of the following riskcriteria were met: (a) home intravenous treatment (self-administered or otherwise) or injury or ulcer treatmentby specialized personnel in the last 30 days; (b) hospitalcare, intravenous hemodialysis or chemotherapy in thelast 30 days; (c) prior hospitalizations lasting 2 or moredays in the 90 days prior to the current infectious episode,and (d) residing in an assisted-living home or long-stayhospital and (3) nosocomial: diagnosis of the infectionafter a minimum of 48 h of hospitalization. In cases oftransfers from other hospitals, the time was consideredfrom the admission to the first center.

-- Clinical and epidemiological: smoking and alcoholism(active consumption was defined as a period of absti-nence of less than a year), antibiotic treatment in the 6months prior to the pneumococcal infection, vaccination

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for pneumococcus with the 23-valent polysaccharide vac-cine, location of the infection, FINE stage19 in the caseof pneumonia, degree of comorbidity measured by theCharlson index, type of tumor (solid or hematologic), evi-dence of distant metastases, neutropenia at the timeof infection (moderate neutropenia: total number ofneutrophils in peripheral blood <1000 cells/mm,3 severeneutropenia <500 cells/mm3) and time elapsed since thelast dose of chemotherapy.

-- Complementary examinations: blood cultures, cultures ofsputum or of other sterile or non-sterile samples, pneu-mococcal antigen in urine or in other fluids, chest X-raypattern.

-- Complications and outcome: pleural effusion, empyema,endotracheal intubation, non-invasive mechanical venti-lation, septic shock, distant septic metastases, overallmortality during hospitalization and mortality related tothe actual pneumococcal infection.

-- Microbiological information: antibiogram and serotypingof isolated pneumococcal strains (since January 2009,all S. pneumoniae isolates have been systematicallydelivered to the Pneumococcal Reference Laboratory,National Microbiology Center, Carlos III Health Institute).The identification of S. pneumoniae was performed byobserving blood from alpha hemolytic, catalase-negativeand optochin-sensitive colonies in agar. For inconclusivecases, we used the bile solubility test and the Slidexpneumo-kit® (bioMérieux, Marcy L’Etoile, France), whichemploys agglutination with latex particles coated in spe-cific antiserum. We studied the sensitivity to penicillin,amoxicillin and cefotaxime using the E-test® (AB-Biodisk,Solna, Sweden) using cutoff points for non-meningeal iso-lates. We also studied the sensitivity to erythromycin,tetracycline, telithromycin, vancomycin, cotrimoxazoleand levofloxacin using a disc-plate (Oxoid) following theCLSI-2011 criteria.20

We performed a descriptive statistical analysis of theharacteristics of the patients with oncohematologic dis-ase using a frequency analysis for quantitative variablesnd the calculation of means, standard deviations, mediansnd ranges for quantitative variables. We then conducted aomparative analysis with the adults patients who had noistory of oncohematologic disease recorded in the sameatabase using Student’s t-test for quantitative variablesnd the chi-squared test for qualitative variables, apply-ng Fisher’s exact test when necessary. In this case, we alsoalculated the corresponding odds ratio (OR) with 95% confi-ence intervals (95% CI). All calculations were performedith the SPSS® version 12.1 software package.

esults

e studied 131 episodes of incident pneumococcal infection112 in males and 19 in females) in 122 patients with onco-ematologic disease (median age: 67 years; range: 34---88).hese episodes were compared with 803 incident episodes

uring the same study period in patients with no oncohema-ologic disease.

The majority of the incident infections in oncohemato-ogical patients were related to healthcare or nosocomial

Pneumococcal infections in oncohematological patients 11

Table 1 Clinical and epidemiological characteristics of the patients in the study.

Variable Oncohematologicpatients (n = 131)

Non-oncohematologicpatients (n = 803)

Significance

Male/female 112/19 565/238 OR: 2.4395% CI: 1.4---4.1

Age 67 (range: 34---88) 66 (range: 15---97) p = 0.02HIV infection 0 54 (6.7%) p = 0.02Active PDUa 0 30 (3.7%) p = 0.02Active smokinga 39 (29.7%) 272 (33.8%) NSActive alcoholisma 15 (11.4%) 93 (11.5%) NS23-Valent vaccine 2 (1.5%) 28 (3.4%) NSHeart failure 14 (10.6%) 122 (15.2%) NSChronic respiratory disease 72 (55%) 448 (55.7%) NSLiver disease 14 (10.6%) 89 (11%) NSDiabetes 39 (29.7%) 192 (24%) NS

drug user; HIV: human immunodeficiency virus.

distantly by other types of infection (Table 3). The majorityof pneumonia cases were cataloged as FINE iv-v (37 cases,71.2%). The most common radiological pattern was lobarcondensation (31 cases), followed by bilateral condensationin more than one lobe (6 cases), unilateral condensation inmore than one lobe (3 cases), unilateral condensation witheffusion (2 cases) and bilateral condensation with effusion(2 cases). Other rare patterns (atelectasis, isolated pleuraleffusion, cavitated condensation, etc.) were seen in 8 cases.The following complications were observed: pleural effusionin 1 case (0.8%), empyema in 1 case (0.8%), shock in 7 cases(5.3%) and the need for endotracheal intubation in 8 cases(6.1%).

Sputum samples were collected in only 8 episodes, with3 resulting positive. Pneumococcal antigen was determined

Table 2 Distribution of neoplasms from the patientsincluded in the study.

Neoplasm Number Percentage131

Solid neoplasms 109 83.2Lung 44 33.6Prostate-testicular 17 13.0Kidney-bladder 12 9.2Colon 8 6.1Liver 5 3.8Stomach 3 2.3Esophagus 2 1.5Breast 3 2.3Skin 3 2.3Others 12 9.2

Hematologic neoplasms 23 17.6Non-Hodgkin’s lymphoma 8 6.1Multiple myeloma 6 4.5Hodgkin’s lymphoma 2 1.5

95% CI: 95% confidence interval; OR: odds ratio; PDU: parenteral

a In the last year.

causes (76 cases, 58%). In 52 (40%) episodes, and therewas a history of receiving antibiotic treatment in the last 6months. The median of the Charlson comorbidity index was 5(range: 2---11). Only 2 patients with oncohematologic diseaseand 28 patients in the control group were documented ashaving received the 23-valent polysaccharide vaccine. Theclinical and epidemiological characteristics of the patientsare summarized in Table 1.

Ninety-three patients (71%) showed active neoplasms.Twenty-two patients had hematologic disease, 108 had solidneoplasms and 1 patient had both types of neoplasm (pul-monary adenocarcinoma and non-Hodgkin’s lymphoma). Themost frequent type of solid neoplasia was lung cancer with44 cases (40.3%). The predominant type of hematologic neo-plasia was non-Hodgkin’s lymphoma with 8 cases (34.7%),followed by leukemia with 7 cases (30%) and multiplemyeloma with 6 cases (26%). The list of incident neoplasmsis summarized in Table 2.

During the 6 months prior to the pneumococcal infection,chemotherapy was administered on 43 occasions (32.8%),radiation therapy was administered on 1 occasion (0.8%) andsurgical eradication was performed on 4 occasions (3.1%).In 28 (21.3%) episodes, the diagnosis of the neoplasm coin-cided with the infection, and in 6 (4.6%) episodes, thepatient or physician rejected implementation of active can-cer treatment. In the remaining 49 episodes, the followingcircumstances occurred: surgical eradication in 25 (19.1%),chemotherapy in 10 (7.6%), and radiation therapy in 6(4.6%), more than 6 months before the pneumococcal infec-tion; hormonal therapy was administered on 6 occasions(4.6%), BCG instillation on 1 occasion (0.8%) and unknownon 1 occasion (0.8%). In 122 of the episodes (93%), therewas no evidence of neutropenia at the time of the pneumo-coccal infection. In 3 episodes (2.3%), the neutropenia wasmoderate, and in 6 episodes (4.6%), it was severe.

The majority of oncohematological patients were diag-nosed with pneumonia (52 cases, 40%) or lower respiratory

tract infections without consolidation (59 cases, 45%). Thesame situation occurred with the control group, with 393cases of pneumonia (48.9%) and 301 cases (37.5%) of lowerrespiratory tract infections without consolidation, followed

Leukemia 7 5.3

One patient had both a solid neoplasm and a hematologic neo-plasm simultaneously.

12 M. Pérez de la Blanca-Burgos et al.

Table 3 Distribution of the infections and the general and attributable mortality in oncohematologic patients (cases) and inthe controls with no oncohematologic condition.

Variable Cases (n = 131) Controls (n = 803) Statistical significancen (%) n (%) p

InfectionPneumonia 52 (40) 393 (48.9) 0.049Non-condensing lower respiratory tract infections 59 (45.1) 301 (37.5) NSPrimary bacteremia 6 (4.6) 16 (2) NSBronchiectasis superinfection 5 (3.8) 17 (2.1) NSMeningitis 3 (2.3) 8 (1) NSAbscesses 2 (1.6) 3 (0.4) NSOtitis 2 (1.5) 15 (1.9) NSPeritonitis 2 (1.5) 9 (1.1) NSEmpyema 0 2 (0.2) NAArthritis 0 1 (0.1) NAOthers 0 38 (4.7) NA

Overall mortality 16 (14.0) 47 (6.2) <0.006Attributable mortality 10 (62.5) 33 (70.2) NS

n: number of patients; NA: not applicable; NS: not significant.

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common was the 23F (2 isolates); among the non-vaccineserotypes, the most common were 6A, 11A, 19A, 31, and33F, with 3 cases in each (Table 4).

When analyzing the results of the sensitivities to the var-ious antibiotics in the population of patients with solid or

Table 4 Distribution of the isolated pneumococcalserotypes in oncohematological patients (cases) and in thecontrols with no oncohematologic condition, according towhether they were included (vaccinated) or not with thepneumococcal vaccine.

Serotypes Cases (n = 38) Controls (n = 197)n (%) n (%)

Non-vaccine 33 (86.8) 170 (86.3)3 2 (5.3) 37 (18.8)6A 2 (5.3) 8 (4.1)7F 2 (5.3) 20 (10.1)11A 3 (7.8) 7 (3.5)19A 3 (7.8) 15 (7.6)20 2 (5.3) 1 (0.5)22F 0 (0.0) 8 (4.1)31 3 (7.8) 2 (1.0)33F 3 (7.8) 2 (1.0)Others 13 (34.2) 70 (35.5)

Vaccine 5 (13.1) 27 (13.7)4 1 (2.6) 2 (1.0)6B 0 (0.0) 2 (1.0)9V 0 (0.0) 3 (1.5)14 1 (2.6) 8 (4.1)18C 0 (0.0) 2 (1.0)

n urine in 60 cases (45.8%) and positive in 22 cases (36.7% ofhe samples). The determination of pneumococcal antigensn other fluids was performed in 8 episodes, which resultedositive in 4 episodes (2 in pleural effusions and 2 in cere-rospinal fluid). The blood cultures were positive in 27 ofhe 75 episodes (36%) in which blood was extracted.

When comparing the characteristics of the oncohemato-ogical patients with those of the control patients (thoseith no oncohematologic disease), we observed that theatients with solid or hematologic neoplasms were moreften male (85.5% vs. 70.4%; OR: 2.43; 95% CI: 1.4---4.1;

< 0.001). Fifty-eight percent of the oncohematologicalatients and 30.6% of the controls showed infections associ-ted with healthcare or nosocomial causes (OR: 3.1; 95% CI:.1---4.5; p < 0.001). The FINE severity indices were higher inatients with neoplasms (82% of cases in patients with onco-ematologic disease FINE iv-v vs. 48% of cases in controls; OR:.0: 95% CI: 2.0---10.0; p < 0.001). The age of the patientsith oncohematologic disease was significantly greater than

hat of the control group (p = 0.02), but once the 38 patientsith inactive neoplasms were excluded from the analysis,

hese differences disappeared.Sixteen patients (12.2%) died during hospitalization; 10

f these deaths were considered related to the pneumococ-al infection (7.6%). The mortality not attributable to theneumococcal infection was significantly higher in patientsith no oncohematologic disease (6 [4.5%] vs. 14 [1.7%]ases in each group; OR: 2.25; 95% CI: 1.2---4.1; p < 0.006).he rate of bacteremia (36% vs. 40.7% of the episodes inhich blood cultures were conducted) and the frequencyf complications (15.2% vs. 21.9%) did not vary significantlyetween the two patient groups.

Among the 38 samples from infections in oncohemato-

ogical patients in which the serotype was obtained, theredominant serotypes were those not included in the VCN-733 isolates, 86.8%) compared to the non-vaccine serotypes5 isolates, 13.1%). Among the vaccine serotypes, the most

19F 1 (2.6) 7 (3.5)23F 2 (5.3) 3 (1.5)

n: number of patients; %: compared to the total isolatedserotypes.

Pneumococcal infections in oncohematological patients

Table 5 Sensitivity to the various antibiotics in oncohe-matological patients (cases) and in the controls with nooncohematologic condition.

Cases Controls Statistical significance(%) (%) p

Penicillin 85 79.7 NSAmoxicillin 94.6 96.2 NSCefotaxime 95.4 97.5 NSErythromycin 64.1 71.5 NSTetracycline 76.1 79.8 NSVancomycin 100 100 NACotrimoxazole 67.1 70.7 NSLevofloxacin 93.1 96.7 p = 0.04

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hematologic neoplasms and comparing them with the groupof patients with no neoplastic disease, we observed that theformer had a slightly greater risk of reduced sensitivity tolevofloxacin (122 [93.1%] sensitive vs. 9 [6.9%] with reducedsensitivity; OR: 0.45; 95% CI: 0.2---0.99; p < 0.043) (Table 5).

Discussion

Patients with severe immunosuppression have a high inci-dence of pneumococcal disease, between 28 and 48 timeshigher than expected in healthy adults.15 Since the intro-duction in 2000 (2001 in Spain) of the VCN-7 vaccine inpediatrics, a reduction has been observed in the infectionscaused by this microorganism and the mortality associatedwith these infections.7,15,21 Few studies have been publishedanalyzing the changes caused in patients with oncohemato-logic conditions.15

The present study provides relevant data on pneumo-coccal disease in this population during the post-vaccineperiod and corroborates some of the findings described inother patient groups.17 We can observe a predominance ofpneumococcal infection episodes in males (85%), mainly inrespiratory tract infections (pneumonia and non-condensingrespiratory infection). This situation is not surprising giventhat the most commonly observed solid neoplasm was thepulmonary neoplasm, which is more prevalent in males andthat often other factors are present that favor pneumo-coccal infection, factors such as smoking and underlyingpulmonary conditions.22,23

It should be noted that the most frequent types ofhematologic neoplasms were non-Hodgkin’s lymphoma andleukemia, followed by multiple myeloma, a condition thatis traditionally described as a risk factor for pneumococcaldisease.24,25

As expected, the majority of infections were consideredto be related to healthcare and nosocomial causes, giventhat the oncohematological patients maintained regularcontact with the healthcare environment, either due torecurrent hospital admissions or periodic care in the out-

patient center. Interestingly, pneumococcal infection wasnot related to the recent administration of chemotherapyand also did not coincide with episodes of neutropenia (in92% of episodes, the neutrophil count was greater than

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000 cells/mm3). This observation supports the concepthat, for patients with oncohematologic disease who presentpisodes of febrile neutropenia, we should select activentibiotics against other gram-positive and gram-negativeicroorganisms, including non-fermenters, as reflected

n the majority of series in the literature.26,27 Based onur findings, we should be cautious when empiricallydministering quinolones to oncohematological patientsho present healthcare- or nosocomial-related pneumonia,

ower respiratory tract infections and exacerbations ofhronic obstructive pulmonary disease because of theossibility of resistance. This is especially the case if theatients have received prophylaxis or prior treatment withhese drugs.7,28 The data on the sensitivity to the otherntibiotics were not significantly different from the rest ofhe general population, although the percentage of strainsith reduced sensitivity to levofloxacin was only 7%, a figure

lightly higher than the 5.2% of the general population inur community (unpublished data) and the rest of theeta-lactam antibiotics (third-generation amoxicillin andephalosporins).

The majority of incident pneumococcal pneumonia inncohematological patients was classified into FINE stages

v-v, which is logical if we consider that this situation usuallyccurs in elderly patients with associated comorbidity andhat the presence of a neoplasm represents adding manyoints to the calculation of the FINE index. It would haverobably been more appropriate to use another infectioneverity classification such as the APACHE scale; however,iven that we are dealing with a database designed in 2006,ll of the necessary parameters for calculating this scaleere not initially collected.

Although we do not have data from the periodmmediately before the pediatric implementation of theneumococcal vaccination with VCN-7, it should be notedhat the oncohematological patients did not show anncrease in the number of complications of the pneu-ococcal infection compared with those observed in the

ontrols, nor was there a greater mortality associatedith the actual pneumococcal infection. In other immuno-

uppressed patient groups such as patients with HIVnfection, an increase in the severity of pneumococcalnfections has been reported in the post-vaccine period,s well as a greater frequency of complications such asmpyema.13

It is worth noting that only 2 patients in our seriesere reported in their histories as having received the 23-alent polysaccharide vaccine. In the control group, only8 patients had been vaccinated. This is probably due tohe fact that, in our community, the at-risk population isnder-vaccinated. We cannot rule out the possibility, how-ver, that a number of patients may have been vaccinatedhile in primary care without it being registered in theiredical history.Although the number of pneumococcal strains that were

erotyped in this group of patients was low, our data agreeith those reported in other patient groups, which show a

hift in the serotypes involved in these infections towardhose not included in the VCN-7.5,29,30 An increase in the

ncidence of these serotypes has already been reported,specially for 6A in the oncohematologic population24 whenompared with healthy adults.5

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The limitations of this study include the fact that it wasonducted in a single center and that the results cannote extrapolated to the entire oncohematological patientopulation in other communities. In addition, given that ourenter opened in January 2002, we do not have access toatient data from the pre-vaccination period. The fact thate could only access results from pneumococcal serotypes

tarting from January 2009 also presents a limitation.evertheless, we believe that these limitations do notetract from the validity of our data, given how much theygree with findings reported in the general population andn other groups of immunosuppressed patients.

In our patient series, the pneumococcal infections inncohematological patients occurred more frequently inales, especially with lung neoplasms, mainly affecting

he respiratory tract and although generally not commu-ity acquired, they were not related to recent exposure tohemotherapy or episodes of neutropenia. In general, theredominate serotypes were those not included in the pneu-ococcal vaccine, and the rates of resistance to antibioticsid not differ from those of the general population exceptor the case of quinolones.

onflicts of interest

he authors have no conflicts of interest to declare.

eferences

1. World Health Organization. Pneumococcal conjugate vaccinefor childhood immunization: WHO position paper. Wkly Epi-demiol Rec. 2007;82:93---104.

2. Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniaecolonisation: the key to pneumococcal disease. Lancet InfectDis. 2004;4:144---54.

3. Bartlett JG, Dowell SF, Mandell LA, File Jr TM, Musher DM,Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis. 2000;31:347---82.

4. Centers for Disease Control and Prevention (CDC). Direct andindirect effects of routine vaccination of children with 7-valentpneumococcal conjugate vaccine on incidence of invasive pneu-mococcal disease --- United States, 1998---2003. MMWR MorbMortal Wkly Rep. 2005;54:893---7.

5. Kyaw MH, Lynfield R, Schaffner W, Craig AS, Hadler J, Rein-gold A, et al. Active Bacterial Core Surveillance of the EmergingInfections Program Network. Effect of introduction of the pneu-mococcal conjugate vaccine on drug-resistant Streptococcuspneumoniae. N Engl J Med. 2006;354:1455---63.

6. Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, FarleyMM, et al. Changing epidemiology of invasive pneumococcal dis-ease among older adults in the era of pediatric pneumococcalconjugate vaccine. J Am Med Assoc. 2005;294:2043---51.

7. Payeras A, Villoslada A, Garau M, Borras M, Pareja A, Bein-golea D, et al. Neumonía neumocócica en la era de lavacuna conjugada heptavalente. Enferm Infecc Microbiol Clin.2011;29:250---6.

8. Whitney CG, Farley MM, Hadler J, Harrison LH, Bennet NM, Lyn-field R, et al. Decline in invasive pneumococcal disease afterthe introduction of protein-polysaccharide conjugate vaccine.

N Engl Med. 2003;348:1737---46.

9. Ardanuy C, Tubau F, Pallares R, Calataud L, Domínguez MA,Rolo D ET-AL>. Epidemiology of invasive pneumococcal dis-ease among adult patients in Barcelona before and after

2

M. Pérez de la Blanca-Burgos et al.

pediatric 7-valent pneumococcal conjugate vaccine introduc-tion, 1997---2007. Clin Infect Dis. 2009;48:57---64.

0. Frazao N, Brito-Avo A, Simas C, Saldanha J, Mato R, NunesS, et al. Effect of the seven-valent conjugate pneumococcalvaccine on carriage and drug resistance of Streptococcus pneu-moniae in healthy children attending day-care centers in Lisbon.Pediatr Infect Dis J. 2005;24:243---52.

1. Mbelle N, Huebner RE, Wasas AD, Kimura A, Chang I, Klug-man KP. Immunogenicity and impact on nasopharyngeal carriageof a nonvalent pneumococcal conjugate vaccine. J Infect Dis.1999;180:1171---6.

2. Obando I, Munoz-Almagro C, Arroyo LA, Tarrago D, Sánchez-Tatay D, Moreno-Pérez D, et al. Pediatric parapneumonicempyema. Spain Emerg Infect Dis. 2008;14:1390---7.

3. Burgos J, Penaranda M, Payeras A, Villoslada A, Curran A, GarauM, et al. Invasive pneumococcal disease in HIV-infected adults:clinical changes after the introduction of the pneumococcalconjugate vaccine in children. J Acquir Inmune Defic Syndr.2012;59:31---8.

4. Van der Poll T, Opal SM. Pathogenesis, treatment, andprevention of pneumococcal pneumonia. Lancet. 2009;374:1543---56.

5. Kyaw M, Rose CE, Fry AM, Singleton JA, Moore Z, Zell E, et al.The influence of chronic illnesses on the incidence of invasivepneumococcal disease in adults. J Infect Dis. 2005;192:377---86.

6. Debbache K, Varon E, Hicheri Y, Legrand P, Donay J-L, RibaudP, et al. The epidemiology of invasive Streptococcus pneumo-niae infections in oncohaematology and haematopoietic stemcell transplant patients in France. Are the serotypes covered bythe available anti-pneumococcal vaccines? Clin Microbiol Infect.2009;15:865---8.

7. McCavit TL, Xuan L, Zhang S, Flores G, Quinn CT. Hospitaliza-tion for invasive pneumococcal disease in a national samplewith sickle cell disease before and after PCV7 licensure. PediatrBlood Cancer. 2012;58:945---9.

8. Kumashi P, Girgawy E, Tarrand JJ, Rolston KV, Raad II, Saf-dar A. Streptococcus pneumoniae bacteremia in patients withcancer. Disease characteristics and outcomes in the era ofescalating drug resistance (1998---2002). Medicine. 2005;84:303---12.

9. Fine M, Auble TE, Yealy DM, Hanusa BH, WIessfeld LA, SingerDE, et al. A prediction rule to identify lowrisk patients withcommunity acquired pneumonia. N Engl J Med. 1997;336:243---50.

0. Clinical, Laboratory Standards Institute. Performance standardsfor antimicrobial susceptibility testing; twentieth informationalsupplement. CLSI document M100-S20. 2010;29:88---91.

1. Comité Asesor de Vacunas de la Asociación Espanola dePediatria. La enfermedad neumocócica y su prevención. Vac-una neumocócica conjugada heptavalente. An Esp Pediatr.2002;56:79---90.

2. Nuorti JP, Butler JC, Farley MM, Harrison LH, McGeer A,Kolczak MS, et al. Cigarette smoking invasive pneumococcal dis-ease. Active Bacterial Core Surveillance Team. N Engl J Med.2000;342:681---9.

3. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factorsfor acquiring pneumococcal infections. Arch Intern Med.1986;146:2179---85.

4. Wong A, Marrie TJ, Garg S, Kellner JD, Tyrrell GJ, and theSPAT Group. Increased risk of invasive pneumococcal disease inhaematological and solid-organ malignancies. Epidemiol Infect.2010;138:1804---10.

5. Kalambokis GN, Christou L, Tsianos EV. Multiple myeloma pre-senting with an acute bacterial infection. Int J Lab Hematol.

2009;31:375---83.

6. Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsisand its mortality rate: actual versus perceived risks. Br J Surg.1991;78:1031---8.

2

Pneumococcal infections in oncohematological patients

27. Figuera Esparza M, Carballo M, Silva M, Figueredo A, Avilán J.Microbiological isolates in patients with febrile neutropenia andhematological neoplasias. Rev Esp Quimioter. 2006;19:247---51.

28. Kern WV, Steib-Bauert M, de With K, Reuter S, Bertz H,

Frank U, et al. Fluoroquinolone consumption and resis-tance in haematology-oncology patients: ecological analysis intwo university hospitals 1999---2002. J Antimicrob Chemother.2005;55:57---60.

3

15

9. Isaacman DJ, McIntosh ED, Reinert RR. Burden of invasivepneumococcal disease and serotype distribution among Strep-tococcus 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.

0. Musher DM. Pneumococcal vaccine-direct and indirect (‘‘herd’’)effects. N Engl J Med. 2006;354:1522---4.