https://orcid.org/0000-0002-2617-1137
Figures
Abstract
Purpose
Streptococcus pneumoniae (Spn) is the primary bacterial cause of lower respiratory tract infections (LRTI) globally, particularly impacting older adults and children. While Spn colonization in children is linked to LRTI, its prevalence, and consequences in adults with comorbidities remain uncertain. This study aims to provide novel data in that regard.
Methods
This prospective study of outpatient adults with chronic diseases was conducted in Colombia. Data on demographics, vaccination, and clinical history was collected in a RedCap database. Nasopharyngeal aspirate samples were examined for Spn colonization using traditional cultures and quantitative—real time polymerase chain reaction (q-rtPCR). Patients were followed for 18 months, with colonization prevalence calculated and factors influencing colonization and its impact on clinical outcomes analyzed through logistic regressions.
Results
810 patients were enrolled, with 10.1% (82/810) identified as colonized. The mean (SD) age was 62 years (±15), and 48.6% (394/810) were female. Major comorbidities included hypertension (52.2% [423/810]), cardiac conditions (31.1% [252/810]), and chronic kidney disease (17.4% [141/810]). Among all, 31.6% (256/810) received the influenza vaccine in the previous year, and 10.7% (87/810) received anti-Spn vaccines. Chronic kidney disease (OR 95% CI; 2.48 [1.01–6.15], p = 0.04) and chronic cardiac diseases (OR 95% CI; 1.62 [0.99–2.66], p = 0.05) were independently associated with Spn colonization. However, colonization was not associated with the development of LRTI (OR 95%CI; 0.64 [0.14–2.79], p = 0.55) or unfavorable outcomes (OR 95% CI;1.17 [0.14–2.79], p = 0.54) during follow-up.
Citation: Olivella-Gomez J, Lozada J, Serrano-Mayorga CC, Méndez-Castillo L, Acosta-González A, Viñán Garcés AE, et al. (2025) The relation of nasopharyngeal colonization by Streptococcus pneumoniae in comorbid adults with unfavorable outcomes in a low-middle income country. PLoS ONE 20(2): e0318320. https://doi.org/10.1371/journal.pone.0318320
Editor: Oriana Rivera-Lozada de Bonilla, Norbert Wiener University, PERU
Received: October 11, 2024; Accepted: January 14, 2025; Published: February 12, 2025
Copyright: © 2025 Olivella-Gomez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data underlying these results has been uploaded as supplementary information.
Funding: This project was funded by M.S.D. Colombia, a subsidiary of Merck & Co., Inc., RAHWAY, NJ, USA and Universidad de La Sabana grant number (MED-285-2020) L.F.R.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Luis Felipe Reyes (L.F.R) recieved funding from M.S.D Colombia for the development of this study.
Introduction
Lower respiratory tract infections (LRTI) are the leading infectious causes of mortality worldwide [1]. According to the Global Burden of Disease (GBD), LRTI etiology is most frequently attributed to microorganisms such as Streptococcus pneumoniae (Spn), Haemophilus influenzae type b (Hib), influenza viruses, and respiratory syncytial virus (RSV), among others [2]. S. pneumoniae is the leading cause of morbidity and mortality due to respiratory infectious diseases worldwide [3]. Notably, the highest burden of pneumococcal disease (PD) has been documented in vulnerable populations, such as the extremes of age and those with chronic comorbid conditions [4]. Several risk factors have been linked with PD in adults, including advanced age, chronic medical comorbidities (i.e., heart disease, chronic lung disease, diabetes mellitus, cancer, and chronic renal disease), and immunocompromising conditions [5, 6]. However, it has been postulated in children that nasopharyngeal pneumococcal colonization (NPC) plays an important role [7].
Nasopharyngeal carriage is considered the first step towards invasive pneumococcal disease (IPD) in children [7]. This colonization has been proposed to be attributed to several mechanisms, including the evasion of mucus entrapment by capsular polysaccharide, biofilm formation, expression of adhesion proteins, inhibition of complement proteins, and release of bacteriocins to mediate competition with local microbiota [8]. It has been controversial to consider Spn NPC as a prerequisite for developing IPD [9]. However, some authors have found a link between the acquisition/carriage by Spn and the development of a respiratory diseases [10–14]. In adults, several risk factors for colonization have been described, such as smoking, living with children, and residence in a nursing home [15] yet the association between Spn NPC and IPD development in adults remains unclear and unexplored.
This study aims to determine the prevalence of Spn NPC and to explore if there is a relationship between Spn NPC and the development of unfavorable outcomes (i.e., development of community-acquired pneumonia (CAP), hospital admission or mortality due to infectious diseases) in adult patients with comorbidities. In addition, it examines factors associated with Spn NPC colonization and describes anti-Spn vaccination rates in patients with comorbidities based on current local guidelines.
Materials and methods
This prospective multicenter cohort study was conducted in adult patients with chronic diseases from four outpatient clinics in Bogotá, Colombia. This retrospective cohort study was done following the strengthening of the reporting of observational studies in epidemiology (STROBE) guidelines [16] and the tenets of the Helsinki declaration. The study protocol and written informed consent were developed by the Translational Science in Infectious Diseases and Critical Care Medicine (TSID-CCM) research group from the Universidad de La Sabana. These documents were reviewed and authorized by the Institutional Review Board/Independent Ethics Committee (IRB/EC) of each participating institutions (CUS 01-20Feb2020, Shaio 301-26Aug2020, IPS-Clínicos 01-20Feb2020, and Baxter 05-01Sep2021). Ethical supervision ensured written informed consent was obtained from all study participants or their authorized representatives.
Inclusion criteria consisted of individuals aged 18 years or older with at least one chronic disease. Comorbidities are defined in S1 Table. Participants were actively attending one of the four participating centers, with recruitment beginning on December 2nd 2020 at two centers, January 2nd 2021 at the third, and September 13th 2021 at the fourth. Recruitment was completed in March 17th 2022, once the target sample size was reached. The exclusion criteria included patients with evidence of respiratory symptoms (e.g., rhinorrhea, fever, or expectoration) or diagnosis of community-acquired pneumonia (CAP) during the prior to 90 days according to the criteria of the American Thoracic Association (ATS)—Infectious Diseases Society of America (IDSA) [17]. Also, subjects admitted to the hospital during the previous 7 days of enrollment or limited to providing biological-type samples were excluded from the study.
Definitions
A patient was considered Spn NPC positive if at least one of the two tests described below yielded a positive result. Spn NPC was defined as the identification of Spn either by conventional culture, confirmed through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF), or by the amplification with sigmoidal curve amplification of both the pneumolysin (ply) and autolysin (lytA) genes using quantitative real-time polymerase chain reaction (q-rtPCR) in nasopharyngeal aspirates (NPA), and evaluated based on the patient’s specific conditions and local guidelines for anti-Spn vaccination [18].
Finally, the unfavorable outcome variable was composed of patients who developed CAP by any cause, including viral pneumonia (CAP diagnosis was determined using the definition of IDSA/ATS guidelines during the follow-up [17] hospitalization due to an infectious cause, whether by Spn or other microorganisms or succumbed to pneumonia or another infectious cause at any point during the follow-up period (i.e., 6, 12 and 18 months after enrollment).
Data collection and laboratory procedures
Data collection was carried out by a dedicated research assistant, who gathered sociodemographic details of medical history, including comorbidities, living conditions, and lifestyle habits. Participants were also required to provide a verifiable vaccination record at baseline. The data collection process used an Electronic Case Report Form (eCRF) developed within the Research Electronic Data Capture (REDCap) platform (version 8.11.11 provided by Vanderbilt University, Nashville, Tenn.), hosted by Universidad de Sabana. Follow-up data was collected by telephone interviews 6, 12, and 18 months after enrollment. This data included information on hospital admissions, reason for hospitalization, symptoms associated with hospitalization, and hospital center where care was received.
For all patients enrolled in the study after signing informed consent, trained nursing staff collected NPA samples with an 8 mm nelaton probe (Medex, INVIMA 2008DM—0001689 R2, Colombia) and 8–10 cc rinsing infusion of physiological saline solution (PSS) of sodium chloride 0. 9% (Baxter, Viaflex) at 10–15 cm in the posterior nostril of each participant according to the guidelines of the WHO (World Health Organization) Pneumococcal Carriage Working Group in 2013 [19].
In the laboratory, 100 μL of nasopharyngeal aspirate (NPA) was immediately inoculated on blood agar and incubated at 37°C +/− 2°C for 24–48 hours in 5% CO2. Alpha-hemolytic colonies were selected, underwent optochin sensitivity testing, and sensitive strains were identified using (MALDI-TOF) mass spectrometry. “Suspected cases” were defined as colonization with Spn when alpha-hemolytic colonies showed optochin sensitivity > 14 mm [20]. “Confirmed cases” had MALDI-TOF scores > 1.8 [21]. Additionally, a q-rtPCR approach targeting ply and lytA genes was employed, adhering to specific criteria for pneumococcal colonization identification, including Ct < 35 [22–24] and characteristic melt curve profiles (S1 File) [25]. Information regarding conventional culture, primer selection, run cycle, and standard curve identification for ply and lytA gene identification and specific criteria for colonization identification can be found in the online supplement (S1 File).
Throughout the follow-up period, phone interviews were systematically conducted with each patient at 6, 12, and 18 months from the enrollment date unless their demise or dissent of participation was previously known. These interviews aimed to gather information on instances of hospitalization, including the cause and duration, and to inquire about the development of pneumonia. If pneumonia occurred, patients were asked to provide their medical records. Then, a detailed chart review assessed the identified etiology and details of antibiotic use, including the duration of therapy and clinical outcomes. In cases where the patient had passed away, details such as the date and cause of death were meticulously recorded. Vaccination status was updated if the patient had been vaccinated during the study period. The inquiry spanned the last 6 months preceding the call.
Statistical analysis
Data were accessed for research purposes on the 13th of November 2023. A descriptive analysis was conducted using measures of central tendency (mean or median) and dispersion (standard deviation or interquartile range), depending on the data distribution, which was assessed using the Shapiro-Wilk test for quantitative variables. For qualitative variables, frequencies and percentages were calculated. The period prevalence of Spn NPC was determined by dividing the number of positive Spn NPC cases by the total number of subjects recruited during the study period. Demographic variables and comorbidities were compared between the positive Spn NPC and negative Spn NPC groups to assess differences, using the chi-square or Fisher’s exact test for categorical variables and the Student’s T-test or Mann-Whitney U test for continuous variables based on their distribution. Missing data was assessed through multiple imputation when variables relevant to the study had 5–20% of missing data, if the percentage was under 5 imputation was not performed; if missing data accounted for more than 20% variables were excluded.
A univariate analysis was performed to identify variables potentially related to Spn NPC and unfavorable outcomes. After univariate analysis a binary multivariate regression model was applied to identify factors associated with Spn NPC, with adjustments made for age to include demographic details upon admission. The stepwise logistic regression model included variables with a significance level of 0.20 or lower from the univariate analysis and with biological plausibility as well as absence of collinearity as identified in a directed acyclic diagram. Finally, a multivariate regression analysis over the 18-month follow-up period was performed to explore the impact of colonization on unfavorable as defined above. This model was adjusted for age, vaccination status, and renal replacement therapy to address potential selection bias due to the significant number of patients undergoing renal replacement therapy. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated from the final model’s coefficients. All statistical analyses were conducted using IBM SPSS Statistics for Mac, version 22.0 (Armonk, NY: I.B.M. Corp).
Results
Between December 2020 and March 2022, 810 patients were enrolled, with 10.1% (82/810) identified as colonized through conventional culture and/or the q-rtPCR method. In the overall cohort, the average age of the study population was 62 years, with a standard deviation of ± 15 years, and females represented 48.6% (394/810) of the cohort. The predominant comorbidity among the studied population was hypertension 52% (423/810), followed by cardiac conditions 31% (252/810), chronic kidney disease (CKD)17.4% (141/810), and immunologic compromise 17.1% (139/810); all the other comorbid conditions are presented in Table 1. Regarding environmental factors, 13.1% (106/810) of the patients lived with small children, and 14.4% (117/810) were smokers. Other detailed demographic and clinical characteristics for the overall cohort and stratified by Spn colonization are provided in (S2 Table).
Regarding vaccination, 31.6% (256/810) of patients had received the influenza vaccine during the prior year, while 10.7% (87/810) had been administered a version of the anti-Spn vaccine before study enrollment. Among those who received the pneumococcal vaccine, 50% (44/87) were administered the PPSV-23, 11.4% (10/87) received PCV-13, and 3.4% (3/87) were given the PSSV+PCV scheme. Notably, 33.3% (29/87) of individuals could not specify the type of pneumococcal vaccine they received but were aware of having received it. Only 1.1% (1/87) reported receiving PCV-10. Further details regarding vaccination within each subgroup based on local guidelines can be found in (Table 2).
Over the 18-month follow-up period, 3.7% (30/810) of the cohort developed pneumonia, comprising 13 cases at 6 months, 13 at 12 months, and 4 cases at 18 months. In total, 20.2% (164/810) of participants were hospitalized for any cause during the follow-up, resulting in 248 admissions: 76 at 6 months, 89 at 12 months, and 83 at 18 months. Among these hospitalizations, 46 were attributed to infectious causes at 6 months, 56 at 12 months, and 40 at 18 months, contributing to 142 hospitalizations included in the composite outcome variable of unfavorable outcome. The mortality rate was 4.1% (34/810) at 6 months, 1.7% (13/776) during the following 6 months, and reached 1.4% (11/763) during the last 6 months for a total of 7.2% (58/810) during the entire 18-month follow-up period. Additional insights into the observed outcomes at each time point are visually presented in (Fig 1), providing a comprehensive overview of the cohort’s trajectory over the specified period.
Flowchart describing the number of samples collected (NPA: Nasopharyngeal Aspirate), the analysis method (CC: Conventional Culture, q-rtPCR: Real-time Polymerase Chain Reaction), the follow-up phases, the proportion of subjects lost during the study period, and the percentages of unfavourable outcomes, including hospitalization, pneumonia cases, and mortality in each phase.
Outcomes
The Spn NPC period prevalence was 10.1% (82/810) during the patient observation period. Over the 18-month follow-up, 25% (203/810) of patients developed any of the three considered outcomes within the unfavorable outcome variable. A multivariate logistic regression was conducted to explore the association between comorbidities and Spn colonization. In this analysis, chronic kidney disease was identified as a risk factor for colonization, showing an odds ratio (OR, [95% CI]) of 2.48 (1.01–6.15), p = 0.04. Similarly, cardiac diseases presented a statistically significant risk factor, albeit crossing the confidence interval, with an OR [95% CI] of 1.62 (0.99–2.66), p = 0.05. Although significant in the univariate analysis, chronic hepatic disease did not demonstrate an association in this multivariate analysis. Details on specific outcomes for the univariate and multivariate analysis can be found in (Fig 2A). Hosmer-Lemeshow test for binary logistic regression models demonstrated the goodness-of-fit test (p = 0.703).
Forrest plots of multivariate analysis for colonization risk factors and its impact on unfavorable outcomes (2A) Risk factors for Spn Colonization. (2B) Risk factors for unfavorable outcomes.
Similarly, a multivariate binary logistic regression analysis was conducted to examine whether colonization by Spn predisposed patients to develop an unfavorable outcome, as previously defined. This analysis, adjusted for age, vaccination status, and the need for renal replacement therapy, revealed that colonization by either traditional culture or q-rtPCR showed no statistically significant association with unfavorable outcomes (OR [95% CI]) of 1.17 (0.69–1.98), p = 0.54. Further information regarding both univariate and multivariate analyses can be found in the online supplement (S3 and S4 Tables). Moreover, a sub-analysis specifically for LTRI development showed that colonization was not a risk factor for LTRI development, taking into account the bias that the low number of events represent (OR [95% CI]) of 0.64 (0.14–2.78), p = 0.55 (S5 Table). Age was demonstrated to be independently associated with unfavorable outcomes in the multivariate analysis (1.81 [1.28–2.58], p < 0.01). As expected, the need for renal replacement therapy emerged as a significant contributor to unfavorable outcomes in the multivariate analysis (5.10 [3.43–7.58], p < 0.01). Specific outcomes from the univariate analysis are detailed in (Fig 2B), and the Hosmer-Lemeshow test for binary logistic regression models demonstrated the goodness-of-fit test (p = 0.548).
Discussion
The reported Spn colonization of 10.1% (82/810) in the present research aligns with findings from prior studies in adults, which have reported a prevalence range of 1–10% [20, 21]; the most recent metanalysis found an overall prevalence of 6% and in the subgroup analysis a prevalence of 2% for adults [26]. Previous research on adult colonization varies in methodology, age range, and sample size, often lacking comorbidity assessments. Abdullahi et al. presented a similar study reported in Kenya in age range. Still, they did not consider comorbidities, reporting a rate of 6.4% (n = 450) in adults >18 years [27], and Palmu et al. reported a 5,23% prevalence in healthy adults >65 years (n = 592) [28]. Conversely, comorbidity-focused studies, such as those published by Heinsbroek et al. and Dayie et al. in Malawi and Ghana, show higher rates (21.3%, 10.0%) in adults with HIV and sickle cell anemia respectively [29, 30]. Studies made by Milucky et al. and Roca-Oporto et al. conducted in high-income countries like the US and Spain reported lower rates (1.8% to 5,6%) in individuals with solid organ transplants and chronic diseases [31, 32]. Notably, patients with influenza-related respiratory symptoms exhibit rates as high as 31% [33]. However, even though Colombia is classified as an upper-middle-income country, this study identified a Spn colonization rate of 5.0% (7/139) in patients with immunocompromise, which is consistent with the rates described by Milucky et al. and Roca-Oporto et al. [31, 32]. Therefore, the presented findings are novel because they assessed the nasopharyngeal colonization by Spn in a broader cohort of patients with multiple chronic comorbid conditions, using traditional cultures and q-rtPCR based technics, making these results more generalizable.
This real-world study found a low anti-Spn vaccination rate among adults with comorbid conditions in Colombia, which agrees with previous studies conducted in Colombia by Severiche et al. and Serrano et al. [4, 34]. Also, the current study found a low colonization rate despite suboptimal vaccination rates per local guidelines. In contrast, prior literature had shown that before the introduction of the conjugate vaccine in state schedules, proportions of culture-based colonization in HIV adult patients were as high as 16% and 18% in Brazil and Uganda, as described by Nicoletti et al. and Blossom et al. [35, 36]. Becker-Dreps et al. found in older adults with general comorbidity a 1.9% colonization rate before the introduction of anti-Spn vaccines in the US [37]. Following the incorporation of conjugate vaccines (PCV 7, 10, 13, 15, and 20), Drayss were found in adults > 65 years from geriatric homes in Germany with low comorbidity levels and colonization rates of 0% [38]. Even though the role that plays anti-Spn vaccines in nasopharyngeal colonization has been controversial, and different factors might affect the colonization rates, this study´s results reinforce the need for more robust vaccination campaigns in adults with chronic comorbid conditions, as it has been described that solid vaccination campaigns could reduce IPD development in adults [39].
Van Hoek and Pekuz et al. studies have indicated a relationship between CKD and IPD [40, 41]. Also, some studies have highlighted better outcomes and survival rates in vaccinated patients with comorbid conditions [42, 43]. However, limited research explores CKD’s link to colonization. Cardiovascular disease (CVD) and heart failure are frequently associated with pneumococcal disease [44–46], but their association with colonization risk remains uncertain across studies [47]. Thus, identifying CKD and chronic cardiac diseases independently associated with nasopharyngeal Spn-colonization, highlights the importance of vaccination in these groups of patients.
Finally, the present study did not find an association between Spn colonization and the development of any of the three unfavorable outcomes, which contradicts the currently available data on children. This finding is novel as, to our knowledge, this study is the first study exploring this relationship in adults with comorbid conditions. One possible explanation for this study´s findings and how they differ from what has been previously reported in children is that adults have, as a result of prior exposure events to Spn, generated an adaptive immune response to Spn proteins, which would confer broad protection from disease caused by all serotypes of Spn. Alternatively, during childhood, these individuals were colonized by versions of Spn that carry capsule types most frequently associated with disease, and now, due to the production of antibodies to these capsule types, they are more likely to be colonized by strains not as capable of causing severe infection. Therefore, further studies are needed to understand the etiology of LRTI and unfordable outcomes in patients with comorbid conditions.
The present study has some limitations that should be mentioned. First, this cohort size is relatively small, potentially impacting the ability to draw statistically significant associations. In addition, only one NPA sampling was performed, which, given the dynamics of Spn colonization, does not allow us to adequately determine whether there is an association between Spn NPC and the development of unfavorable outcomes. However, the study was powered to identify statistical differences, and more importantly, to the best of our knowledge, this is the first study assessing nasopharyngeal colonization in adults with comorbidities, rendering these findings applicable to a significant demographic subset. Second, this study found a low prevalence of pneumococcal colonization that could be attributed to the inherent difficulty in culturing Spn. Nevertheless, the study employed molecular tests to augment the likelihood of successful isolations, enhancing the precision of the analysis. Furthermore, this study overlapped with the COVID-19 pandemic, which may have impacted social dynamics, underestimating the actual behavior of the colonization phenomena [48].
In conclusion, this novel study reinforces existing evidence that comorbidities such as CKD and cardiac diseases increase susceptibility to pneumococcal colonization. These findings underscore the imperative need for vaccination in this population. Vaccination rates, particularly for pneumococcal vaccines, were suboptimal, highlighting the urge to implement adherence to vaccination guidelines. Finally, this research found that nasopharyngeal colonization by Spn was not associated with unfavorable outcomes in this population, including the development of LRTI. There is a need for further research to understand the complex interactions between colonization, comorbidities, and clinical outcomes.
Supporting information
S1 Table. Comorbidities included in the study and their definition.
https://doi.org/10.1371/journal.pone.0318320.s001
(PDF)
S2 Table. Heterogeneity amongst colonized and non-colonized groups of patients.
https://doi.org/10.1371/journal.pone.0318320.s002
(PDF)
S3 Table. Univariate and multivariate analysis for factors associated with colonization.
https://doi.org/10.1371/journal.pone.0318320.s003
(PDF)
S4 Table. Univariate and multivariate analysis for colonization as a risk factor for unfavorable outcomes.
https://doi.org/10.1371/journal.pone.0318320.s004
(PDF)
S5 Table. Spn NPC as a risk factor for LTRI, multivariate analysis.
https://doi.org/10.1371/journal.pone.0318320.s005
(PDF)
S1 File. Materials, methods, and protocols used in the study.
https://doi.org/10.1371/journal.pone.0318320.s006
(PDF)
Acknowledgments
We extend our gratitude to all the patients who participated in the study for their trust, as well as to the healthcare clinics whose collaboration was essential. We also acknowledge the research team from the TSID_CCM group for their dedication and commitment, which were crucial to the completion of this study for their contribution and support in this investigation.
References
- 1.
Organization WH. The Top 10 Causes of Death Globally 2020. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.
- 2. Anderson R, Feldman C. The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy. Int J Mol Sci. 2023;24(13). Epub 20230703. pmid:37446214.
- 3. Cedrone F, Montagna V, Del Duca L, Camplone L, Mazzocca R, Carfagnini F, et al. The Burden of Streptococcus pneumoniae-Related Admissions and In-Hospital Mortality: A Retrospective Observational Study between the Years 2015 and 2022 from a Southern Italian Province. Vaccines (Basel). 2023;11(8). Epub 20230804. pmid:37631892.
- 4. Severiche-Bueno DF, Severiche-Bueno DF, Bastidas A, Caceres EL, Silva E, Lozada J, et al. Burden of invasive pneumococcal disease (IPD) over a 10-year period in Bogota, Colombia. Int J Infect Dis. 2021;105:32–9. Epub 20210211. pmid:33582374.
- 5. Fukuda H, Onizuka H, Nishimura N, Kiyohara K. Risk factors for pneumococcal disease in persons with chronic medical conditions: Results from the LIFE Study. Int J Infect Dis. 2022;116:216–22. Epub 2022/01/06. pmid:34986403.
- 6. Grant LR, Meche A, McGrath L, Miles A, Alfred T, Yan Q, et al. Risk of Pneumococcal Disease in US Adults by Age and Risk Profile. Open Forum Infect Dis. 2023;10(5):ofad192. Epub 2023/05/14. pmid:37180598.
- 7. Weiser JN, Ferreira DM, Paton JC. Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol. 2018;16(6):355–67. Epub 2018/03/31. pmid:29599457.
- 8. Subramanian K, Henriques-Normark B, Normark S. Emerging concepts in the pathogenesis of the Streptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen. Cell Microbiol. 2019;21(11):e13077. Epub 2019/06/30. pmid:31251447.
- 9. Nunes MC, Jones SA, Groome MJ, Kuwanda L, Van Niekerk N, von Gottberg A, et al. Acquisition of Streptococcus pneumoniae in South African children vaccinated with 7-valent pneumococcal conjugate vaccine at 6, 14 and 40 weeks of age. Vaccine. 2015;33(5):628–34. Epub 2014/12/30. pmid:25541213.
- 10. Sleeman KL, Daniels L, Gardiner M, Griffiths D, Deeks JJ, Dagan R, et al. Acquisition of Streptococcus pneumoniae and nonspecific morbidity in infants and their families: a cohort study. Pediatr Infect Dis J. 2005;24(2):121–7. Epub 2005/02/11. pmid:15702039.
- 11. Jousimies-Somer HR, Savolainen S, Ylikoski JS. Comparison of the nasal bacterial floras in two groups of healthy subjects and in patients with acute maxillary sinusitis. J Clin Microbiol. 1989;27(12):2736–43. Epub 1989/12/01. pmid:2592539.
- 12. Mogdasy MC, Camou T, Fajardo C, Hortal M. Colonizing and invasive strains of Streptococcus pneumoniae in Uruguayan children: type distribution and patterns of antibiotic resistance. Pediatr Infect Dis J. 1992;11(8):648–52. Epub 1992/08/01. pmid:1523077.
- 13. Ciftci E, Dogru U, Aysev D, Ince E, Guriz H. Investigation of risk factors for penicillin-resistant Streptococcus pneumoniae carriage in Turkish children. Pediatr Int. 2001;43(4):385–90. Epub 2001/07/27. pmid:11472584.
- 14. Faden H, Waz MJ, Bernstein JM, Brodsky L, Stanievich J, Ogra PL. Nasopharyngeal flora in the first three years of life in normal and otitis-prone children. Ann Otol Rhinol Laryngol. 1991;100(8):612–5. Epub 1991/08/01. pmid:1908199.
- 15. Almeida ST, Paulo AC, Froes F, de Lencastre H, Sa-Leao R. Dynamics of Pneumococcal Carriage in Adults: A New Look at an Old Paradigm. J Infect Dis. 2021;223(9):1590–600. Epub 2020/09/03. pmid:32877517.
- 16. Vandenbroucke JP, von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Int J Surg. 2014;12(12):1500–24. Epub 2014/07/22. pmid:25046751.
- 17. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45–e67. Epub 2019/10/02. pmid:31573350.
- 18.
Morales GE. FRG, Ministerio de Salud y Protección Social. Lineamientos Técnicos y Operativos para la transición de la Vacuna Polisacárida contra el Neumococo de PCV10 a PCV13 en Colombia 2022 2022. https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/VS/PP/ET/lineamiento-tecnico-operativo-transicion-vacuna-polisacarda-contra-neumococo-pcv10-pcv13-colombia-2022.pdf.
- 19. Satzke C, Turner P, Virolainen-Julkunen A, Adrian PV, Antonio M, Hare KM, et al. Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization Pneumococcal Carriage Working Group. Vaccine. 2013;32(1):165–79. pmid:24331112.
- 20. Burckhardt I, Panitz J, Burckhardt F, Zimmermann S. Identification of Streptococcus pneumoniae: Development of a Standardized Protocol for Optochin Susceptibility Testing Using Total Lab Automation. Biomed Res Int. 2017;2017:4174168. Epub 20170319. pmid:28401155.
- 21. Dubois D, Segonds C, Prere MF, Marty N, Oswald E. Identification of clinical Streptococcus pneumoniae isolates among other alpha and nonhemolytic streptococci by use of the Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry system. J Clin Microbiol. 2013;51(6):1861–7. Epub 20130410. pmid:23576536.
- 22. Carvalho Mda G, Tondella ML, McCaustland K, Weidlich L, McGee L, Mayer LW, et al. Evaluation and improvement of real-time PCR assays targeting lytA, ply, and psaA genes for detection of pneumococcal DNA. J Clin Microbiol. 2007;45(8):2460–6. Epub 20070530. pmid:17537936.
- 23. Gladstone RA, Lo SW, Lees JA, Croucher NJ, van Tonder AJ, Corander J, et al. International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact. EBioMedicine. 2019;43:338–46. Epub 20190416. pmid:31003929.
- 24. Epping L, van Tonder AJ, Gladstone RA, The Global Pneumococcal Sequencing C, Bentley SD, Page AJ, et al. SeroBA: rapid high-throughput serotyping of Streptococcus pneumoniae from whole genome sequence data. Microb Genom. 2018;4(7). Epub 20180615. pmid:29870330.
- 25. Valdarchi C, Dorrucci M, Mancini F, Farchi F, Pimentel de Araujo F, Corongiu M, et al. Pneumococcal carriage among adults aged 50 years and older with co-morbidities attending medical practices in Rome, Italy. Vaccine. 2019;37(35):5096–103. Epub 20190705. pmid:31285086.
- 26. Lozada J, Gomez JO, Serrano-Mayorga CC, Vinan Garces AE, Enciso V, Mendez-Castillo L, et al. Streptococcus pneumoniae as a colonizing agent of the Nasopharynx - Oropharynx in adults: A systematic review and meta-analysis. Vaccine. 2024;42(11):2747–57. Epub 2024/03/22. pmid:38514352.
- 27. Abdullahi O, Nyiro J, Lewa P, Slack M, Scott JA. The descriptive epidemiology of Streptococcus pneumoniae and Haemophilus influenzae nasopharyngeal carriage in children and adults in Kilifi district, Kenya. Pediatr Infect Dis J. 2008;27(1):59–64. pmid:18162940.
- 28. Palmu AA, Kaijalainen T, Saukkoriipi A, Leinonen M, Kilpi TM. Nasopharyngeal carriage of Streptococcus pneumoniae and pneumococcal urine antigen test in healthy elderly subjects. Scand J Infect Dis. 2012;44(6):433–8. Epub 20120121. pmid:22263905.
- 29. Heinsbroek E, Tafatatha T, Phiri A, Ngwira B, Crampin AC, Read JM, et al. Persisting high prevalence of pneumococcal carriage among HIV-infected adults receiving antiretroviral therapy in Malawi: a cohort study. AIDS. 2015;29(14):1837–44. Epub 2015/07/29. pmid:26218599.
- 30. Dayie N, Tetteh-Ocloo G, Labi AK, Olayemi E, Slotved HC, Lartey M, et al. Pneumococcal carriage among sickle cell disease patients in Accra, Ghana: Risk factors, serotypes and antibiotic resistance. PLoS One. 2018;13(11):e0206728. Epub 20181108. pmid:30408061.
- 31. Milucky J, Carvalho MG, Rouphael N, Bennett NM, Talbot HK, Harrison LH, et al. Streptococcus pneumoniae colonization after introduction of 13-valent pneumococcal conjugate vaccine for US adults 65 years of age and older, 2015–2016. Vaccine. 2019;37(8):1094–100. Epub 20190123. pmid:30685247.
- 32. Roca-Oporto C, Cebrero-Cangueiro T, Gil-Marques ML, Labrador-Herrera G, Smani Y, Gonzalez-Roncero FM, et al. Prevalence and clinical impact of Streptococcus pneumoniae nasopharyngeal carriage in solid organ transplant recipients. BMC Infect Dis. 2019;19(1):697. Epub 20190806. pmid:31387529.
- 33. Krone CL, Wyllie AL, van Beek J, Rots NY, Oja AE, Chu ML, et al. Carriage of Streptococcus pneumoniae in aged adults with influenza-like-illness. PLoS One. 2015;10(3):e0119875. Epub 20150319. pmid:25789854.
- 34. Serrano-Mayorga CC, Ibanez-Prada ED, Restrepo-Martinez JM, Garcia-Gallo E, Duque S, Severiche-Bueno DF, et al. The potential impact of PCV-13, PCV-15 and PCV-20 vaccines in Colombia. Vaccine. 2024;42(7):1435–9. Epub 2024/02/10. pmid:38336559.
- 35. Nicoletti C, Brandileone MC, Guerra ML, Levin AS. Prevalence, serotypes, and risk factors for pneumococcal carriage among HIV-infected adults. Diagn Microbiol Infect Dis. 2007;57(3):259–65. Epub 2007/02/13. pmid:17292578.
- 36. Blossom DB, Namayanja-Kaye G, Nankya-Mutyoba J, Mukasa JB, Bakka H, Rwambuya S, et al. Oropharyngeal colonization by Streptococcus pneumoniae among HIV-infected adults in Uganda: assessing prevalence and antimicrobial susceptibility. Int J Infect Dis. 2006;10(6):458–64. Epub 2006/09/26. pmid:16997591.
- 37. Becker-Dreps S, Kistler CE, Ward K, Killeya-Jones LA, Better OM, Weber DJ, et al. Pneumococcal Carriage and Vaccine Coverage in Retirement Community Residents. J Am Geriatr Soc. 2015;63(10):2094–8. Epub 20151012. pmid:26456473.
- 38. Drayss M, Claus H, Hubert K, Thiel K, Berger A, Sing A, et al. Asymptomatic carriage of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Group A Streptococcus and Staphylococcus aureus among adults aged 65 years and older. PLoS One. 2019;14(2):e0212052. Epub 2019/02/09. pmid:30735539.
- 39. 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. pmid:25785969.
- 40. van Hoek AJ, Andrews N, Waight PA, Stowe J, Gates P, George R, et al. The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England. J Infect. 2012;65(1):17–24. Epub 20120303. pmid:22394683.
- 41. Pekuz S, Soysal A, Akkoc G, Atici S, Yakut N, Gelmez GA, et al. Prevalence of Nasopharyngeal Carriage, Serotype Distribution, and Antimicrobial Resistance of Streptococcus pneumoniae among Children with Chronic Diseases. Jpn J Infect Dis. 2019;72(1):7–13. Epub 20180831. pmid:30175734.
- 42. Bond TC, Spaulding AC, Krisher J, McClellan W. Mortality of dialysis patients according to influenza and pneumococcal vaccination status. Am J Kidney Dis. 2012;60(6):959–65. Epub 2012/06/15. pmid:22694948.
- 43. Gilbertson DT, Guo H, Arneson TJ, Collins AJ. The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients. Nephrol Dial Transplant. 2011;26(9):2934–9. Epub 2011/02/15. pmid:21317410.
- 44. Feldman C, Anderson R. Recent advances in our understanding of Streptococcus pneumoniae infection. F1000Prime Rep. 2014;6:82. Epub 20140904. pmid:25343039.
- 45. Corrales-Medina VF, Musher DM, Shachkina S, Chirinos JA. Acute pneumonia and the cardiovascular system. Lancet. 2013;381(9865):496–505. Epub 20130116. pmid:23332146.
- 46. Viasus D, Garcia-Vidal C, Manresa F, Dorca J, Gudiol F, Carratala J. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J Infect. 2013;66(1):27–33. Epub 20120911. pmid:22981899.
- 47. Branche AR, Yang H, Java J, Holden-Wiltse J, Topham DJ, Peasley M, et al. Effect of prior vaccination on carriage rates of Streptococcus pneumoniae in older adults: A longitudinal surveillance study. Vaccine. 2018;36(29):4304–10. Epub 20180602. pmid:29871816.
- 48. Facciola A, Lagana A, Genovese G, Romeo B, Sidoti S, D’Andrea G, et al. Impact of the COVID-19 pandemic on the infectious disease epidemiology. J Prev Med Hyg. 2023;64(3):E274–E82. Epub 20231101. pmid:38125993.