Derivation and Validation of the Risk Evaluation Score for Pneumonia Involving Resistant Entities (RESPIRE)

Study Design and Setting

This is a single-center, non-profit observational study with two sequential phases: an initial retrospective phase and a subsequent prospective phase. Patients were enrolled during two consecutive, non-overlapping periods: from January 1, 2022 to December 31, 2023 (retrospective cohort), and from January 1, 2024 to December 31, 2025 (prospective cohort).

The study was conducted in a hospital setting and is monocentric, carried out at the Emergency Department and the Emergency Sub-Intensive Care Unit of Azienda Ospedaliero Universitaria Careggi, in collaboration with the Units of Microbiology and Virology and Infectious Diseases. Careggi is a large academic hospital that serves as the local hospital for a population of approximately 650,000 inhabitants and acts as a tertiary referral center for about 1,600,000 people.

Retrospective Phase (Derivation Cohort)

During the first observational retrospective phase (2 years), data were collected to establish a retrospective derivation cohort composed of patients with microbiologically confirmed etiological diagnoses of pneumonia. The derivation cohort includes patients who underwent microbiological investigations aimed at identifying the etiological diagnosis of pneumonia within the first 48 hours from admission to Azienda Ospedaliero Universitaria Careggi.

Following an initial screening of microbiological test requests received by the Microbiology and Virology Laboratory-using dedicated software containing microbiological investigations and electronic medical records of patients with pneumonia-patients who underwent diagnostic testing to determine the etiological agent of pneumonia (bacterial, viral, or fungal) on respiratory samples (considered the diagnostic gold standard for etiological assessment) within 48 hours of hospital admission were identified. Subsequently, patients' medical records were reviewed by the investigators to construct the final cohort database.

During the retrospective phase, patients with microbiologically confirmed bacterial, fungal, or viral pneumonia were included in order to create the retrospective cohort. Cases in which no bacterial, fungal, or viral pathogen was identified were excluded. Only patients with positive culture results and available antimicrobial susceptibility testing were selected. Patients with bacterial pneumonia caused by multidrug-resistant (MDR) pathogens identified on culture constituted the study group, whereas patients with bacterial pneumonia caused by non-MDR pathogens constituted the control group. MDR pneumonia was defined as pneumonia caused by bacterial pathogens exhibiting acquired non-susceptibility to at least one agent in three or more antimicrobial categories.

Only patients with a confirmed etiological diagnosis of pneumonia and positive culture results were included, in order to avoid the inclusion of false-negative cases. Negative respiratory culture results (reported in the literature in approximately 40-60% of cases) could have introduced potential selection bias, as culture-negative results do not allow exclusion of pneumonia caused by MDR pathogens.

Prospective Phase (Validation Cohort)

During the second observational prospective phase (2 years), data were collected to establish a prospective cohort of Emergency Department patients, on which the performance of the clinical score derived from the retrospective cohort was evaluated in a purely observational manner.

The validation cohort includes patients diagnosed with pneumonia who underwent microbiological investigations on respiratory samples in the Emergency Department to assess the etiological agent. No additional diagnostic tests were performed beyond routine clinical practice. Only patients with pneumonia who underwent microbiological investigations on respiratory samples at the clinician's discretion were included. After an initial phase, only patients with positive respiratory culture results were included, for the same reasons described above.

The Units of Emergency Medicine and Surgery and Integrated Clinical Assessment and In-Hospital Emergency Pathways were responsible for patient assessment, enrollment, sample collection, and data collection. The Unit of Microbiology and Virology was responsible for identifying microbiological test requests received by the laboratory during the study period and for extracting microbiological data.

Study Objectives

The primary objective of the study is to derive a clinical predictive score for MDR pathogen-related pneumonia in patients diagnosed with pneumonia presenting to the Emergency Department and/or admitted to the hospital from the community.

Secondary objectives are:

1. validation of the derived clinical score in a prospective patient cohort;
2. comparison of the performance of the developed score in predicting MDR-related pneumonia with validated scores such as DRIP, Shorr, Park, Shindo, Aliberti, and Schreiber, as well as the ATS/IDSA HCAP criteria;
3. analysis of positive predictive value (PPV), negative predictive value (NPV), specificity, sensitivity, positive and negative likelihood ratios (LR+ and LR-), and optimal cut-off values;
4. assessment of score calibration in both the derivation and validation cohorts;
5. evaluation of clinical impact using decision curve analysis.

• RESPIRE score (Other): RESPIRE is a clinical risk prediction score developed to estimate the probability of pneumonia caused by multidrug-resistant (MDR) pathogens. In this observational study, the RESPIR-E score is derived and validated using routinely collected clinical and microbiological data. The score is not applied to guide clinical decision-making and does not influence diagnostic or therapeutic management. It is evaluated solely for observational and research purposes.

Primary outcomes

• Clinical score (RESPIRE) derivation [Within 48 hours from Emergency Department presentation / hospital admission.]: The primary objective of the study is to derive a clinical predictive score for MDR pathogen-related pneumonia in patients diagnosed with pneumonia presenting to the Emergency Department and/or admitted to the hospital from the community.

Secondary outcomes

• validation of the derived clinical score in a prospective patient cohort; [Within 48 hours of the index Emergency Department presentation or hospital admission for pneumonia.]: validation of the derived clinical score in a prospective patient cohort;
• comparison of the performance of the developed score in predicting MDR-related pneumonia with validated scores [Within 48 hours of the index Emergency Department presentation or hospital admission for pneumonia.]: comparison of the performance of the developed score in predicting MDR-related pneumonia with validated scores such as DRIP, Shorr, Park, Shindo, Aliberti, and Schreiber, as well as the ATS/IDSA HCAP criteria (Measure: Area under the curve,sensibility, specificity, PPV, NPV, +LR, -LR)
• PPV, NPV, specificity, sensitivity, LR+, LR-, Youden [Within 48 hours of the index Emergency Department presentation or hospital admission for pneumonia.]: analysis of positive predictive value (PPV), negative predictive value (NPV), specificity, sensitivity, positive and negative likelihood ratios (LR+ and LR-), and optimal cut-off values;
• Calibration [Within 48 hours of the index Emergency Department presentation or hospital admission for pneumonia.]: assessment of score calibration in both the derivation and validation cohorts;
• Clinical utiliy [Within 48 hours of the index Emergency Department presentation or hospital admission for pneumonia.]: evaluation of clinical impact using decision curve analysis (eg. treatment variation %)

Sex: All, ages: 18 Years to 90 Years

Inclusion Criteria:

All patients:

* aged ≥18 years
* who underwent respiratory sample collection within 48 hours of hospital admission and had subsequent positive culture results oleading to a confirmed etiological diagnosis of community-acquired pneumonia (CAP)
* Pneumonia was clinically defined by the presence of two or more clinical signs or symptoms (body temperature <36.0°C or >38.0°C; respiratory rate >20 breaths/min; oxygen saturation on room air <90%; arterial partial pressure of oxygen <60 mmHg; cough; sputum production; white blood cell count <4,000/μL or >10,000/μL; bandemia >10%), in addition to radiographic evidence of a new parenchymal opacity or cavitation.
* Only patients with positive respiratory culture results were included in the analysis.

During the prospective phase, only patients whose microbiological samples were collected in the Emergency Department were enrolled.

Exclusion Criteria:

* informed consent was not provided
* age was <18 years or >90 years
* pregnant
* pneumonia occurred after more than 48 hours from hospital admission (hospital-acquired pneumonia).

• Results publication: Pelagatti L, De Marco M, Bosco E, Catalucci T, Gilardoni M, Mangani F, Spinicci M, Bartoloni A, Rossolini GM, Nazerian P, Vanni S. RESPIRE Score: Derivation and Validation of a New Risk Score for Prediction of Community-acquired Pneumonia Caused by Resistant Pathogens. Open Forum Infect Dis. 2026 May 21;13(6):ofag319. doi: 10.1093/ofid/ofag319. eCollection 2026 Jun. PMID 42238377