Pneumococcal Nasopharyngeal Colonization as Predictor of Community-Acquired Pneumonia (CAP) in Adults With Chronic Diseases.

Streptococcus pneumoniae (the pneumococcus) is responsible for more than 5 million deaths a year globally (Aliberti et al., 2016; Reyes et al., 2017). This opportunistic Gram-positive bacterium is the most frequently identified bacteria in patients with CAP, acute meningitis, and otitis in children and adults (Paterson et al., 2010; Hinojosa et al., 2014).

The pneumococcal disease has changed during the last decade due to universal pneumococcal vaccination programs, especially in children, patients with chronic pulmonary diseases, and patients older than 65 years old. Now, serotypes thought to be not clinically significant are frequently identified in patients with pneumococcal diseases (Imohl et al., 2015; Vlachopoulos et al., 2015; Cilloniz et al., 2016; Diao et al., 2016; Suzuki et al., 2017).

However, mortality and morbidity associated with pneumococcal infection in adults have remained relatively steady during the last decades (Jain et al., 2015; Bellew et al., 2018; Wunderink et al., 2018). Several hypotheses have been generated to explain this phenomenon. Among the most studied, researchers have documentedthat circulating pneumococcal serotypes are different now, and thus, currently available vaccines may not be as useful to prevent invasive pneumococcal diseases now (Aliberti et al., 2013; Cilloniz et al., 2016).

Moreover, adults are not frequently vaccinated with the pneumococcal vaccine, and only a very restrictive group of patients receive the vaccine. In Colombia, it is not known whether even that restrictive group of adults with an indication for a pneumococcal vaccine have been vaccinated, following national and international guidelines. More importantly, it is unknown whether other groups of patients with chronic medical diseases might benefit from receiving this vaccine.

Importantly, it is also unknown, which are the most prevalent serotypes causing colonization and invasive infections in adults with chronic diseases in Colombia.

We have recently carried out a multicenter, multinational, worldwide study designed to characterize better the etiology of CAP (the most frequent infection caused by the pneumococcus) (Aliberti et al., 2016; Carugati et al., 2016; Gramegna et al., 2018; Restrepo et al., 2018; Radovanovic et al., 2019).

In this study, we enrolled more than 3,700 patients in six continents, finding that S. pneumoniae continues to be the most frequent bacterial pathogen identified in patients with CAP worldwide. However, in this study, we also documented that the pneumococcal vaccination rate is meager (data not yet published). Thus, we firmly believe that identifying whether pneumococcal vaccination is adequate in our country (Colombia), and more importantly, which are the most prevalent pneumococcal serotypes colonizing the nasopharyngeal epithelium of patients with chronic medical conditions, might help us to identify new indications for pneumococcal vaccination and to help decrease the burden of pneumococcal diseases.

Therefore, here we will attempt to provide new information to characterize better pneumococcal nasopharyngeal colonization of patients with chronic medical diseases, its implications, its overtime dynamics, and how this colonization might be associated with CPA development. Moreover, here we will be able to characterize vaccination compliance and how this previous vaccination might modify the natural course of pneumococcal disease (i.e., nasopharyngeal colonization precedes pneumococcal pneumonia). Finally, here we will carry out real-world evidence, prospective study evidence that will provide generalizable data for clinicians around the globe.

This is real-world evidence, prospective, observational, multicenter, a cohort study of consecutive patients.

Inclusion Criteria

All consecutive ambulatory patients that assist to 5 outpatient clinics with chronic diseases such as heart failure, HBP, chronic cardiac arrhythmias, rheumatic diseases, non-cystic-fibrosis bronchiectasis, COPD, among others, with the following inclusion criteria will be included in the study:

• Older than 18 years old
• Patients assisting to cardiology, pulmonology, endocrinology or rheumatology clinic in participating centers
• Patients in whom vaccination information is available and confirmed in the medical records (this information will also be confirmed during the patient's interview)
• Patients that sign informed consent form.

Exclusion Criteria

• Patients diagnosed with CAP during the past 90 days
• Patients admitted to the hospital during the last 7 days
• Patients with limitation to provide biological samples

Baseline procedures

After identifying potential study subjects, informed consent will be obtained for interested patients, and a unique identification number will be assigned for each study' participant. Under any circumstance, patients will receive more than one identification number. Then, demographic data, past medical history, comorbid conditions, recent hospitalization, and biological samples will be gathered.

We will perform a nasopharyngeal swap to identify which patients are colonized with S. pneumoniae and to identify which are the most prevalent pneumococcal serotypes. We will draw 20cc of blood to identify inflammatory biomarkers, and 30cc urine samples will be collected for laboratory analyses.

Biological samples processing

After collecting samples in ambulatory clinics during study visits, these will be referred to our centralized research laboratory localized in the Universidad de La Sabana to carry out laboratory experiments. All nasopharyngeal swaps will be culture for pneumococcal identification; if S. pneumoniae is identified, we will characterize in our laboratory pneumococcal serotypes. Moreover, we will perform rtPCR to better identify and quantify pneumococcal colonization in the nasopharyngeal swabs.

We will also quantify serum biomarkers of inflammation, using commercially available ELISA kits. Importantly, all laboratory personnel will be blinded to patients' characteristics and clinical outcomes, to ensure data quality and avoid observer bias.

Follow-ups and outcome determination

As the primary aim of this study is to determine the role of nasopharyngeal colonization in the development of CAP or IPD; after identifying patients colonized by S. pneumoniae during baseline experiments, patients will be followed every month by phone and every 6 months in our outpatient clinics to identify patients that develop CAP or IPD.

Patients will be asked to report any hospital visit (ER visit, hospital admission, and ICU admission) to the study coordinator and to bring discharge summaries provided by hospitals. Patients will be a follow-up for 2 consecutive years. During follow-ups, sample collection will be performed to determine whether patients develop nasopharyngeal colonization or change its systemic inflammatory profile. Samples will be collected and analyzed as baseline procedures.