Expanded Diagnostic Strategy in Older Adults Hospitalized With Community-Acquired Acute Respiratory Infection

This is a pragmatic, controlled, open-label, cluster-randomized crossover trial conducted in two hospital wards at Hospital General Universitario de Elche, Spain. The study population will consist of patients aged 65 years or older hospitalized with community-acquired acute respiratory infection.

The two hospital wards will constitute the study clusters. During the first two-month study period, one ward will be randomly assigned to the expanded diagnostic strategy and the other to the conventional diagnostic strategy. After a two-month washout period, the ward-level strategies will be crossed over for a second two-month study period. Individual participants will receive only the diagnostic strategy assigned to their hospital ward during the corresponding study period.

The expanded diagnostic strategy will include multiplex respiratory PCR using the BIOFIRE Pneumonia Panel plus, including detection of selected antimicrobial resistance genes; bedside lung ultrasound using the BLUE protocol; and serial procalcitonin measurements. The results will be integrated into a predefined diagnostic and therapeutic algorithm to support decisions regarding antibiotic initiation, continuation, modification, de-escalation, and discontinuation.

Participants assigned to the conventional diagnostic strategy will receive usual diagnostic assessment and antimicrobial management. Etiological diagnostic tests will be performed according to routine clinical practice and at the discretion of the treating physician.

The primary objective is to determine whether the expanded diagnostic strategy reduces the total duration of antibiotic therapy compared with conventional diagnostic management. Secondary assessments will include high-impact antibiotic use, antibiotic escalation and de-escalation, microbiological diagnosis and time to diagnosis, detection of multidrug-resistant microorganisms, infectious complications, hospital and intensive care unit length of stay, intensive care unit admission, in-hospital and 30-day mortality, recurrence of infection requiring antimicrobial therapy, 30-day hospital readmission, and antibiotic-related adverse events.

An exploratory economic evaluation of the expanded diagnostic strategy is also planned from the perspective of the Spanish National Health System.

• Expanded Diagnostic Strategy (Diagnostic test): A protocolized diagnostic strategy combining multiplex respiratory PCR using the BIOFIRE Pneumonia Panel plus, bedside lung ultrasound using the BLUE protocol, and serial procalcitonin measurements. Diagnostic results are integrated into a predefined algorithm to support decisions regarding antibiotic initiation, continuation, modification, de-escalation, and discontinuation.
• Conventional Diagnostic Strategy (Diagnostic test): Conventional diagnostic assessment and antimicrobial management according to usual clinical practice. Etiological diagnostic tests are performed at the discretion of the treating physician.

Primary outcomes

• Total Duration of Antibiotic Therapy [From hospital admission through 30 days after hospital discharge]: Total antibiotic exposure, calculated as the sum of days of therapy for all antibiotics received for the index acute respiratory infection, including antibiotic therapy administered during hospitalization and antibiotic therapy prescribed at hospital discharge. Each antibiotic received on a given calendar day contributes one day of therapy; therefore, days of concomitant antibiotic therapy are counted separately for each antibiotic.

Secondary outcomes

• Duration of High Impact Antibiotic Therapy [From hospital admission through 30 days after hospital discharge]: Total exposure to high-impact antibiotics, calculated as the sum of days of therapy for all high-impact antibiotics received for the index acute respiratory infection. High-impact antibiotics are predefined as levofloxacin, moxifloxacin, piperacillin-tazobactam, ceftaroline, ceftobiprole, cefiderocol, cefepime, ceftazidime-avibactam, ceftolozane-tazobactam, carbapenems, vancomycin, and linezolid. Each antibiotic received on a given calendar day contributes one day of therapy; concomitant antibiotics are counted separately.
• Antibiotic De-escalation [From hospital admission through 30 days after hospital discharge]: Proportion of participants in whom antibiotic therapy is de-escalated during the index hospitalization or after discharge. Antibiotic de-escalation is defined as switching from a high-impact antibiotic to a low-impact antibiotic or discontinuing antibiotic therapy, according to the predefined classification in the study protocol.
• Antibiotic Escalation [From hospital admission through 30 days after hospital discharge]: Proportion of participants requiring escalation to high-impact antibiotic therapy for the index acute respiratory infection. Antibiotic escalation is defined as the need to change to an antibiotic classified as high-impact according to the predefined classification in the study protocol.
• Pathogen Detection by Pneumonia Panel PCR [Within the first 24 hours after hospital admission]: Proportion of participants in whom at least one pathogen is detected by the multiplex pneumonia panel PCR performed on a respiratory sample.
• Time to Microbiological Diagnosis [From hospital admission to hospital discharge (assessed at 30 days after discharge)]: Time in hours from hospital admission to the availability of the microbiological result establishing the microbiological diagnosis.
• Detection of Multidrug-Resistant Microorganisms [From hospital admission through 30 days after hospital discharge]: Proportion of participants in whom at least one multidrug-resistant microorganism is detected in any microbiological sample. Multidrug-resistant microorganisms are defined as methicillin-resistant Staphylococcus aureus (MRSA); Enterobacterales producing extended-spectrum beta-lactamases (ESBL), AmpC beta-lactamases, or carbapenemases; Pseudomonas aeruginosa resistant to at least one antibiotic in each of the following classes: penicillins, cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides; carbapenem-resistant Acinetobacter baumannii; and Stenotrophomonas maltophilia.
• Respiratory Infection-Related Complications [From hospital admission through 30 days after hospital discharge]: Proportion of participants who develop at least one complication related to the index acute respiratory infection, including empyema, sepsis, lung abscess, acute respiratory distress syndrome, multiorgan failure, or venous thromboembolism.
• Hospital Length of Stay [From hospital admission to hospital discharge (assessed at 30 days after discharge)]: Total number of days from hospital admission to hospital discharge.
• Intensive Care Unit Admission [From hospital admission to hospital discharge (assessed at 30 days after discharge)]: Proportion of participants requiring admission to the intensive care unit (ICU) during the index hospitalization.
• Intensive Care Unit Length of Stay [From hospital admission to hospital discharge (assessed at 30 days after discharge)]: Total number of days spent in the intensive care unit (ICU) during the index hospitalization among participants requiring ICU admission.
• In-Hospital Mortality [From hospital admission to hospital discharge (assessed at 30 days after discharge)]: Proportion of participants who die from any cause during the index hospitalization.
• 30-Day Mortality After Hospital Discharge [Within 30 days after hospital discharge]: Proportion of participants who die from any cause within 30 days after hospital discharge.
• Recurrence of Respiratory Infection Requiring Antibiotic Therapy [From hospital admission through 30 days after hospital discharge]: Proportion of participants who develop a new episode of respiratory infection requiring a new course of antibiotic therapy during the index hospitalization or within 30 days after hospital discharge.
• 30-Day Hospital Readmission [Within 30 days after hospital discharge]: Proportion of participants requiring hospital readmission for any cause within 30 days after hospital discharge.
• Antibiotic-Related Adverse Events [From hospital admission through 30 days after hospital discharge]: Proportion of participants who experience at least one adverse event considered related to antibiotic therapy, including phlebitis and Clostridioides difficile infection.
• Healthcare Costs [From hospital admission through 30 days after hospital discharge]: Total direct healthcare costs associated with antimicrobial therapy and the diagnostic procedures included in the expanded diagnostic strategy. Costs will include antimicrobial therapy, serial procalcitonin measurements, bedside lung ultrasound, and multiplex pneumonia panel PCR testing.
• Cramér's V Coefficient for Association Between Lung Ultrasound BLUE Profile and Microbiological Diagnostic Category [During the index hospitalization, with final outcome assessment at 30 days after hospital discharge]: The association between the presence or absence of a pneumonia-compatible lung ultrasound BLUE profile (ultrasound profile present/absent) and microbiological diagnostic category (bacterial, viral, mixed bacterial-viral, or no microbiological diagnosis) will be measured using Cramér's V coefficient. Lung ultrasound will be performed according to the BLUE protocol, and microbiological categories will be determined using tests performed during the index hospitalization. Cramér's V will be calculated from a 2 × 4 contingency table, yielding a single unitless numerical value ranging from 0 (no association) to 1 (maximum association). Participants with insufficient microbiological data will be excluded. Diagnostic category distributions according to ultrasound findings will also be reported descriptively.
• Cramér's V Coefficient for the Association Between PLAPS and Microbiological Diagnostic Category [During the index hospitalization, with final outcome assessment at 30 days after hospital discharge]: The association between the presence or absence of posterolateral alveolar and/or pleural syndrome (PLAPS) on lung ultrasound (PLAPS present/absent) and microbiological diagnostic category (bacterial, viral, mixed bacterial-viral, or no microbiological diagnosis) will be measured using Cramér's V coefficient. Lung ultrasound will be performed according to the BLUE protocol, and microbiological categories will be determined using tests performed during the index hospitalization. Cramér's V will be calculated from a 2 × 4 contingency table, yielding a single unitless numerical value ranging from 0 (no association) to 1 (maximum association). Participants with insufficient microbiological data will be excluded. Diagnostic category distributions according to ultrasound findings will also be reported descriptively.
• Cramér's V Coefficient for the Association Between B' Profile and Microbiological Diagnostic Category [During the index hospitalization, with final outcome assessment at 30 days after hospital discharge]: The association between the presence or absence of a B' lung ultrasound profile (B' profile present/absent) and microbiological diagnostic category (bacterial, viral, mixed bacterial-viral, or no microbiological diagnosis) will be measured using Cramér's V coefficient. Lung ultrasound will be performed according to the BLUE protocol, and microbiological categories will be determined using tests performed during the index hospitalization. Cramér's V will be calculated from a 2 × 4 contingency table, yielding a single unitless numerical value ranging from 0 (no association) to 1 (maximum association). Participants with insufficient microbiological data will be excluded. Diagnostic category distributions according to ultrasound findings will also be reported descriptively.
• Cramér's V Coefficient for the Association Between A/B Profile and Microbiological Diagnostic Category [During the index hospitalization, with final outcome assessment at 30 days after hospital discharge]: The association between the presence or absence of an A/B lung ultrasound profile (A/B profile present/absent) and microbiological diagnostic category (bacterial, viral, mixed bacterial-viral, or no microbiological diagnosis) will be measured using Cramér's V coefficient. Lung ultrasound will be performed according to the BLUE protocol, and microbiological categories will be determined using tests performed during the index hospitalization. Cramér's V will be calculated from a 2 × 4 contingency table, yielding a single unitless numerical value ranging from 0 (no association) to 1 (maximum association). Participants with insufficient microbiological data will be excluded. Diagnostic category distributions according to ultrasound findings will also be reported descriptively.
• Cramér's V Coefficient for the Association Between C Profile and Microbiological Diagnostic Category [During the index hospitalization, with final outcome assessment at 30 days after hospital discharge]: The association between the presence or absence of a C lung ultrasound profile (C profile present/absent) and microbiological diagnostic category (bacterial, viral, mixed bacterial-viral, or no microbiological diagnosis) will be measured using Cramér's V coefficient. Lung ultrasound will be performed according to the BLUE protocol, and microbiological categories will be determined using tests performed during the index hospitalization. Cramér's V will be calculated from a 2 × 4 contingency table, yielding a single unitless numerical value ranging from 0 (no association) to 1 (maximum association). Participants with insufficient microbiological data will be excluded. Diagnostic category distributions according to ultrasound findings will also be reported descriptively.
• Cramér's V Coefficient for the Association Between Pleural Effusion and Microbiological Diagnostic Category [During the index hospitalization, with final outcome assessment at 30 days after hospital discharge]: The association between the presence or absence of pleural effusion on lung ultrasound (pleural effusion present/absent) and microbiological diagnostic category (bacterial, viral, mixed bacterial-viral, or no microbiological diagnosis) will be measured using Cramér's V coefficient. Lung ultrasound will be performed according to the BLUE protocol, and microbiological categories will be determined using tests performed during the index hospitalization. Cramér's V will be calculated from a 2 × 4 contingency table, yielding a single unitless numerical value ranging from 0 (no association) to 1 (maximum association). Participants with insufficient microbiological data will be excluded. Diagnostic category distributions according to ultrasound findings will also be reported descriptively.

Sex: All, ages: 65 Years to any

Inclusion Criteria:

* Age ≥ 65 years.
* Hospital admission to the Internal Medicine or Infectious Diseases ward for a community-acquired acute respiratory infection.
* Acute respiratory infection defined by the presence of at least two of the following criteria, with at least one being a clinical criterion:
* Clinical criteria: new-onset cough or worsening of pre-existing cough; purulent sputum production or changes in usual sputum characteristics; new-onset dyspnea or worsening of pre-existing dyspnea; pleuritic chest pain; abnormal respiratory sounds (crackles, rhonchi, or wheezing); fever (temperature ≥ 38°C) or hypothermia (temperature < 36°C).
* Laboratory criteria: leukocytosis (white blood cell count > 11,000/µL or neutrophil count > 8,200/µL) or C-reactive protein ≥ 20 mg/L.
* Radiological criteria: new pulmonary infiltrate or worsening of a pre-existing pulmonary infiltrate on chest imaging.
* No alternative diagnosis considered more likely to explain the clinical presentation, according to the treating physician.

Exclusion Criteria:

* Charlson Comorbidity Index ≥ 5.
* Imminent death with a life expectancy < 24 hours.
* Admission to the intensive care unit (ICU) directly from the Emergency Department or within the first 24 hours after admission to the hospital ward.
* Diagnosis of a solid-organ or hematologic malignancy with active oncologic treatment within the previous 3 months.
* Immune-mediated disease treated with immunosuppressive or immunomodulatory drugs.
* Transplant recipient.
* Treatment with prednisone ≥ 20 mg/day (or equivalent) for ≥2 weeks.
* Human immunodeficiency virus (HIV) infection with an absolute CD4 count < 200 cells/µL.
* Profound neutropenia (< 100 cells/µL).
* Refusal to participate in the study or concurrent participation in another study.
* Previous inclusion in this study.

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• Félix Gutiérrez Rodero, MD, PhD, Study chair, Hospital General Universitario de Elche / Universidad Miguel Hernández
• Mar Masiá Canuto, MD, PhD, Study chair, Hospital General Universitario de Elche / Universidad Miguel Hernández