Lower Respiratory Tract Infections (LRTIs), encompassing community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and pulmonary tuberculosis (PTB), remain among the primary infectious causes of mortality worldwide [1]. Effective management relies on prompt initiation of targeted or broad-spectrum antimicrobial therapy, appropriate source control, and early recognition of non-responding or refractory cases [2].

In routine clinical practice, evaluating treatment response relies heavily on clinical parameters (defervescence, stabilization of hemodynamic and respiratory indices) and inflammatory serum biomarkers such as C-Reactive Protein (CRP) and Procalcitonin (PCT) [3]. However, clinical indices can be blunted by host immunocompromise, elderly age, or underlying chronic obstructive pulmonary disease (COPD) [4].

Diagnostic imaging; specifically plain chest radiography (CXR) and High-Resolution Computed Tomography (HRCT) of the chest; plays a central role in confirming pulmonary parenchymal involvement [5]. While CXR remains the primary screening tool, HRCT offers superior resolution, enabling precise characterization of elementary lesions such as ground-glass opacities (GGO), lobar consolidation, centrilobular nodularity, tree-in-bud patterns, pulmonary necrosis, cavitation, and pleural space complications [6].

Despite the widespread utilization of thoracic imaging, the direct correlation between initial radiological extent/pattern and early clinical or microbiological response to antimicrobial therapy remains insufficiently defined [7]. While radiological resolution typically lags behind clinical recovery by weeks or months, specific baseline radiological markers; such as multi-lobar consolidation, necrotic breakdown, or pleural effusions; may signal high pathogen load, impaired local tissue vascularization, poor drug penetration, or refractory antimicrobial resistance [8].

This study was undertaken to evaluate the correlation between baseline radiological findings on chest radiographs and HRCT with clinical and microbiological response to antimicrobial therapy, and to identify independent imaging predictors of early treatment failure in adult patients presenting with pulmonary infections.

Study Design and Setting

This prospective observational cohort study was conducted across the Departments of Pharmacology and Radiodiagnosis at Khaja Bandanawaz University–Faculty of Medical Sciences; a tertiary care academic hospital over a 12-month period (Feb 2025 to Jan 2026). The protocol was approved by the Institutional Ethics Committee, and written informed consent was obtained from all patients or their legal guardians prior to enrollment in accordance with the Declaration of Helsinki.

Patient Selection

Adult patients admitted with clinical and radiological evidence of acute lower respiratory tract infection were evaluated sequentially.

Inclusion Criteria:

• Adults aged ≥18 years.
• Acute LRTI characterized by at least two clinical features: fever (>38.0^oC or hypothermia < 36.0 ^oC), purulent sputum, cough, dyspnea, pleuritic chest pain, or altered mental status.
• Confirmed parenchymal pulmonary opacity on baseline chest radiograph and non-contrast chest HRCT performed within 24 hours of presentation.
• Agreement to complete serial clinical, microbiological, and radiological evaluations over a 28-day follow-up.

Exclusion Criteria:

• Non-infectious pulmonary parenchymal diseases (e.g., idiopathic pulmonary fibrosis, acute respiratory distress syndrome [ARDS] of non-pulmonary etiology, pulmonary embolism, radiation pneumonitis, hypersensitivity pneumonitis).
• Known active lung malignancy or prior pulmonary resection.
• Severe terminal comorbid states with an expected survival < 7 days.
• Inability or contraindication to undergo chest HRCT.

Imaging Acquisition and Radiological Scoring

Baseline chest radiographs (posterior-anterior [PA] view) and unenhanced high-resolution computed tomography (64-slice Somatom Sensation, Siemens Healthineers; 120 kVp, 100 mAs, 1.0 mm slice reconstruction with sharp B70 kernel) were performed upon admission.

Radiological images were evaluated independently by two experienced radiologists blinded to clinical treatment pathways and microbiological results (kappa = 0.88 for inter-observer agreement).

Parameters Evaluated:

1. Elementary Lesions: Presence and distribution of Consolidation (with/without air bronchograms), Ground-Glass Opacity (GGO), Centrilobular Nodules, Tree-in-Bud pattern, Cavitation/Necrosis, Interstitial Thickening, and Pleural Effusion.
2. Lobar Distribution: Single lobe vs. Multi-lobar (> 3 lobes) involvement; Unilateral vs. Bilateral involvement.
3. HRCT Severity Score: Calculated using a validated 25-point visual scoring system [9]. Each of the five lung lobes (right upper, right middle, right lower, left upper, left lower) was scored from 0 to 5 based on the percentage of anatomical involvement:

• Score 0: 0% involvement
• Score 1: < 5% involvement
• Score 2: 5% - 25% involvement
• Score 3: 26% - 50% involvement
• Score 4: 51% - 75% involvement
• Score 5: > 75% involvement
• Total Score: Sum of all five lobes (range: 0 - 25). High severity was defined as a score > 15/25.

  Microbiological Workup and Antimicrobial Regimens

  Sputum samples (Gram stain, Ziehl-Neelsen/Auramine-Rhodamine stain for acid-fast bacilli [AFB], routine aerobic bacterial/fungal culture, and GeneXpert MTB/RIF) were obtained prior to initiating antimicrobial therapy. Dual sets of blood cultures, urinary Streptococcus pneumoniae and Legionella pneumophila antigens, and multiplex respiratory viral PCR panels were performed.

  Empirical antimicrobial therapy was prescribed according to institutional guidelines based on LRTI severity (ATS/IDSA guidelines for CAP and HAP) [10]. De-escalation or modification to targeted therapy was carried out upon receipt of definitive antimicrobial susceptibility testing (AST) results.

  Clinical Outcome Metrics

  Patients were evaluated daily during hospitalization and at outpatient follow-up visits (Days 7, 14, and 28).

  • Early Treatment Failure (ETF, Day 7): Defined as clinical deterioration requiring ICU transfer/mechanical ventilation, persistent fever (> 38.0^oC) or hypothermia beyond Day 5, worsening oxygenation (PaO₂/ FiO₂ ratio drop > 50 mmHg), or > 50% progression of pulmonary opacities on repeat chest radiograph at Day 7 [11].
  • Time to Clinical Stability (TCS): Days required to reach all of the following parameters: temperature ≤ 37.8 ^oC, heart rate ≤ 100 bpm, respiratory rate ≤ 24 breaths/min, systolic BP ≥ 90 mmHg, and SpO₂ ≥ 92% on room air [12].
  • 28-Day Mortality: All-cause mortality within 28 days of enrollment.

  Statistical Analysis

  Sample size estimation indicated that 260 patients were required to detect a 15% difference in early treatment failure rates between high and low HRCT score groups with 80% power (beta = 0.20) and alpha = 0.05.

  Data were analyzed using SPSS version 28.0 (IBM Corp., Armonk, NY). Continuous variables are expressed as mean ± SD or median (IQR) and compared using the Student's t-test or Mann-Whitney U test. Categorical data are presented as counts (%) and analyzed using the Chi-Square (chi^2) test or Fisher’s exact test. Correlations between HRCT severity score and continuous clinical/biomarker variables were calculated using Pearson’s (r) or Spearman’s (rho) correlation coefficients. Multivariate logistic regression models were built using stepwise variable selection to identify independent radiological predictors of early treatment failure (ETF). p-values < 0.05 were considered statistically significant.

Demographic, Microbiological, and Baseline Radiological Features

A total of 280 patients were enrolled and completed the 28-day follow-up. The mean age was 54.2 ± 15.8 years, with 170 males (60.7%) and 110 females (39.3%). Based on clinical presentation, 168 patients (60.0%) were diagnosed with CAP, 78 (27.9%) with HAP/VAP, and 34 (12.1%) with primary/reactivation PTB.

Microbiological etiology was established in 238 cases (85.0%):

• Bacterial Pathogens (n=182, 65.0%): Streptococcus pneumoniae (n=48), Klebsiella pneumoniae (n=42), Pseudomonas aeruginosa (n=36), Staphylococcus aureus (n=28, including 12 MRSA), and Escherichia coli (n=28).
• Viral Pathogens (n=38, 13.6%): Influenza A/B, SARS-CoV-2, Respiratory Syncytial Virus.
• Mycobacterial Pathogens (n=34, 12.1%): Mycobacterium tuberculosis.
• Fungal / Polymicrobial (n=26, 9.3%): Aspergillus fumigatus, mixed anaerobes.

Baseline radiological characteristics stratified by disease etiology are summarized in Table 1.

Table 1. Baseline HRCT Radiological Patterns Stratified by Clinical Diagnosis (N=280)

Correlation of Radiological Findings with Early Treatment Failure (ETF)

Early Treatment Failure (ETF) at Day 7 occurred in 58 patients (20.7% across the entire cohort; 13.1% in CAP, 38.5% in HAP/VAP, and 17.6% in PTB). Overall 28-day mortality was 8.6% (n = 24).

As presented in Table 2, patients who experienced ETF demonstrated significantly higher baseline HRCT severity scores (17.8 ± 3.9 vs. 12.2 ± 4.8, p < 0.001) and a higher prevalence of baseline high-risk radiological features:

• Multi-lobar involvement (ge 3 lobes): ETF rate was 2% in multi-lobar cases compared to 11.2% in single/two-lobe involvement (p < 0.001).
• Pulmonary Cavitation / Necrosis: ETF rate was 3% in patients with baseline cavitation vs. 15.8% in non-cavitary cases (p < 0.001).
• Bilateral Pleural Effusion: ETF rate was 7% vs. 16.9% in unilateral/absent effusion (p < 0.001).

Table 2. Univariate Analysis of Baseline Radiological Parameters Associated with Early Treatment Failure at Day 7

Quantitative Correlation: HRCT Severity vs. Clinical Kinetics

Pearson's correlation coefficient analysis revealed strong quantitative relationships between baseline HRCT severity score and clinical/biochemical recovery kinetics:

• Time to Clinical Stability (TCS): Baseline HRCT score showed a strong positive correlation with days required to achieve clinical stability (r = 0.642, p < 0.001). Patients with HRCT score > 15 required a median of 8.5 days (IQR: 6–12) to achieve stability compared to 4.0 days (IQR: 3–6) in those with HRCT score > 15 (p < 0.001).
• Biomarker Resolution Kinetics: Baseline HRCT score correlated with delayed clearance of C-Reactive Protein at Day 7 (r=0.584, p<0.001) and Procalcitonin at Day 7 (r = 0.612, p < 0.001).
• Duration of Antimicrobial Therapy: Total duration of parenteral antimicrobial therapy correlated directly with baseline HRCT score (r = 0.628, p < 0.001).

Multivariate Regression Analysis: Independent Radiological Predictors

Stepwise multivariate logistic regression analysis was performed to isolate independent baseline radiological predictors of Early Treatment Failure at Day 7 after controlling for age, sex, APACHE II score, baseline immunosuppression, and initial microbiological appropriateness (Table 3).

After adjusting for clinical confounders:

• Presence of Pulmonary Cavitation/Necrosis was the strongest independent radiological predictor of treatment failure (aOR = 3.84, 95% CI:1.82 - 8.12, p < 0.001).
• Bilateral Pleural Effusion independently tripled the risk of ETF (aOR = 3.15, 95% CI:1.42 - 6.98, p = 0.005).
• Severe Consolidation (>50% zone involvement) remained an independent risk factor (aOR = 2.92, 95% CI:1.45 - 5.88, p = 0.003).
• HRCT Severity Score > 15 doubled the likelihood of 7-day treatment failure (aOR = 2.68, 95% CI:1.32 - 5.44, p = 0.006).

Table 3. Multivariate Logistic Regression Model for Independent Radiological Predictors of Early Treatment Failure (Day 7)

*Adjusted for age, APACHE II score, baseline immunosuppression, serum procalcitonin, and appropriateness of initial empiric antibiotic regimen.

The clinical management of lower respiratory tract infections requires rapid, accurate identification of patients at high risk for therapeutic failure or delayed clinical recovery [13]. This prospective study provides quantitative evidence that baseline high-resolution computed tomography (HRCT) metrics and specific elementary radiological patterns serve as independent predictors of response to antimicrobial therapy.

Pathophysiological Basis of High-Risk Radiological Patterns

Our multivariate regression analysis established that pulmonary cavitation/necrosis (aOR = 3.84), bilateral pleural effusions (aOR = 3.15), and dense consolidation (aOR = 2.92) are strong independent drivers of early treatment failure.

1. Pulmonary Cavitation and Necrosis: Tissue necrosis and cavitation arise from intense local neutrophilic infiltration, microvascular thrombosis, and bacterial toxin release (e.g., aureus Panton-Valentine leukocidin or P. aeruginosa elastase) [14]. The resulting avascular, necrotic core hinders adequate antibiotic penetration, creating sheltered microenvironments where bacterial loads remain high [15]. Furthermore, cavitary lesions are frequently associated with secondary polymicrobial superinfections and high risk of relapse [16].
2. Dense Multi-lobar Consolidation: Extensive lobar consolidation reflects dense fibrinopurulent exudate filling alveolar spaces across multiple anatomical segments [17]. This severe spatial load impairs local pulmonary compliance and creates significant intra-pulmonary shunting (V/Q mismatch), leading to refractory hypoxemia [18].
3. Bilateral Pleural Effusions: Parapneumonic pleural effusions indicate systemic inflammatory spillover and extensive visceral pleural involvement [19]. Complicated effusions or empyema fluid possess an acidic, fibrin-rich microenvironment that inactivates certain antimicrobial classes (e.g., aminoglycosides) and necessitates invasive source control (pigtail catheter insertion or chest tube drainage) beyond systemic pharmacotherapy alone [20].

HRCT Scoring vs. Clinical Biomarker Kinetics

While inflammatory serum biomarkers such as C-Reactive Protein and Procalcitonin provide systemic measures of infection control, their kinetics can be delayed or confounded by steroid therapy, underlying renal impairment, or host immunosuppression [21]. In our study, baseline HRCT severity score (> 15/25) correlated strongly with time to clinical stability (r = 0.642) and prolonged requirement for parenteral antimicrobial therapy.

Quantitative HRCT scoring offers an objective, structural baseline that complements biomarker monitoring [22]. Patients presenting with high HRCT severity scores should be recognized as high-risk candidates who warrant early microbiological escalation (e.g., broad-spectrum coverage for resistant Gram-negative bacilli or MRSA), aggressive supportive care, and early repeat imaging if clinical defervescence is not achieved within 48 to 72 hours [23].

Diagnostic Integration and Antimicrobial Stewardship

Understanding the correlation between initial radiological extent and treatment response reinforces antimicrobial stewardship principles [24]. Slow radiological resolution is a well-documented phenomenon; radiographic opacities frequently persist or lag behind clinical cure by 4 to 8 weeks [25].

However, distinguishing between expected "radiological lag" in a clinically improving patient and true "early treatment failure" in a deteriorating patient relies on correlating radiological baseline features with clinical trajectory [26]. Knowing that a patient with baseline multi-lobar consolidation and cavitation has a predictably longer time to clinical stability prevents unnecessary, premature antibiotic switching when the patient is otherwise hemodynamically stable and defervescing [27].

STUDY LIMITATIONS

Several limitations must be acknowledged. First, as a single-center study at a tertiary hospital, our cohort included a higher proportion of severe HAP/VAP and complex tuberculous cases than seen in primary care. Second, follow-up HRCT scans were not performed routinely at Day 7 for all patients to avoid unnecessary radiation exposure; repeat imaging at Day 7 was restricted to plain chest radiography unless clinical deterioration prompted repeat CT. Third, dynamic contrast-enhanced CT was not utilized, which might provide additional insights into parenchymal perfusion and pulmonary microvascular thrombosis [28].

Quantitative baseline HRCT evaluation and specific imaging phenotypes; specifically pulmonary cavitation, severe multi-lobar consolidation, and bilateral pleural effusions; strongly correlate with delayed clinical stabilization and early failure of empirical antimicrobial therapy in pulmonary infections. Incorporating quantitative radiological risk stratification alongside routine microbiological testing and inflammatory biomarker tracking enables early identification of non-responding patients, guides timely therapeutic adjustments, and optimizes clinical outcomes in lower respiratory tract infections.

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