Radiologic progression with minimal functional decline in cystic fibrosis: Insights from a prospective study

Abstract

BACKGROUND

Timely identification and monitoring of lung disease progression are key components of effective management in patients with cystic fibrosis (CF). Pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans are commonly used to assess disease progression in these patients. Determining which modality provides the most sensitive and reliable assessment is crucial for establishing effective disease monitoring guidelines, particularly in India, where national guidelines are lacking.

AIM

To assess the progression of lung disease in patients with CF using a combination of HRCT and PFTs.

METHODS

A total of 32 patients with CF were prospectively enrolled from the outpatient clinic and followed longitudinally. Clinical and physiological parameters, including age, spirometric indices, and HRCT based Bhalla scores, were evaluated at baseline and after one-year follow-up. Paired comparisons between baseline and follow-up HRCT scores, as well as baseline and follow-up PFT parameters, were performed using a two-tailed paired t-test to assess statistically significant changes over the follow-up period. Pearson correlation coefficient (r) was used to evaluate the relationship between HRCT scores and spirometric parameters at each individual time point (baseline and follow-up). A P value < 0.05 was considered statistically significant.

RESULTS

Of the 32 patients, 18 were female and 14 were male, with a mean age of 86.33 months (range: 48-192 months). The mean Bhalla score demonstrated a statistically significant increase from 5.50 at baseline to 8.25 at one-year follow-up (P < 0.001), representing an average percentage increase of 50%. In contrast, spirometric parameters, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC showed a non-significant decline of 2.9%-5.2% over the study period (P > 0.05).

CONCLUSION

Despite significant radiological progression of structural lung damage detected by HRCT, pulmonary function parameters remained relatively stable. These findings suggest that PFTs may be less sensitive in detecting progressive structural deterioration in CF, underscoring the value of HRCT as a sensitive tool for disease monitoring and early detection of worsening lung disease.

Key Words: Cystic fibrosis; High-resolution computed tomography chest; Pulmonary function test; Bhalla scoring system; Bronchiectasis

Core Tip: This study conducted a longitudinal follow-up of pediatric patients with cystic fibrosis (CF) using a combination of high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). The findings demonstrated that HRCT was superior to PFTs in identifying worsening lung disease. HRCT based Bhalla scores showed a marked increase, with an approximately 50% worsening after one year of follow-up compared to baseline. In contrast, pulmonary function indices, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio, demonstrated only minimal and statistically non-significant declines ranging from 2.9% to 5.2%. These results underscore that HRCT is a more sensitive modality than PFT for assessing disease progression in CF.

INTRODUCTION

Cystic fibrosis (CF) is an inherited condition transmitted in an autosomal recessive manner, caused by mutations in the gene responsible for producing the CF transmembrane conductance regulator protein, located on chromosome 7[1]. CF is a multisystem disorder characterized by dysfunction of the exocrine glands, primarily leading to persistent respiratory infections, pancreatic enzyme deficiency, and various related complications in untreated individuals. Approximately 90% of patients who survive beyond the neonatal stage exhibit pulmonary manifestations, with end-stage lung disease being the predominant cause of mortality[2].

The diagnosis is typically confirmed through a combination of genotyping, nasal potential difference measurement, sweat chloride testing, and the immunoreactive trypsinogen test. Imaging serves as a supportive tool in identifying disease manifestations affecting the sinuses, chest, and abdominal organs[3].

CF is characterized by the production of thick, viscous mucus that obstructs the airways, leading to bacterial entrapment and initiation of a chronic inflammatory cascade. This process results in a vicious cycle of airway obstruction, tissue injury, immune activation, and recurrent infection, ultimately culminating in airway scarring and fibrosis. Common pathogenic organisms, particularly pseudomonas aeruginosa and aspergillus species, play a central role in perpetuating and amplifying this airway damage[3].

It is widely accepted that early and aggressive therapy can delay or halt the progression of lung disease in patients with CF and thereby improve clinical outcomes. Consequently, close monitoring of disease progression is essential to identify early signs of deterioration and to institute timely interventions aimed at preventing further lung damage[4]. Following the initial diagnosis of CF, continuous monitoring is essential to evaluate disease progression and response to therapy.

Pulmonary function tests (PFTs) have traditionally been regarded as the gold standard for disease monitoring in children aged six years and older. However, PFTs primarily reflect functional impairment and are only indirectly related to the underlying structural lung damage[4,5].

A chest X-ray is a quick, cost effective and widely accessible imaging tool for evaluating lung changes in CF; however, due to its low spatial resolution, it only provides a general morphological overview of lungs-detecting findings such as atelectasis, consolidation, or pleural effusion-while often missing subtle abnormalities, especially in the early stages of CF[6,7].

In contrast, high-resolution computed tomography (HRCT) owing to its high spatial resolution allows for the detection of minute structural changes within the bronchi, bronchioles, and lung parenchyma. It plays a vital role in identifying hallmark CF-related abnormalities such as bronchiectasis, peribronchial thickening, mucus plugging, and air trapping[6-8].

HRCT has therefore been adopted by some CF centers as part of routine surveillance, in conjunction with PFTs, to evaluate disease progression[9,10]. Nevertheless, given the heterogeneity of the CF population, it remains unclear in Indian context whether HRCT or PFTs are more sensitive in detecting early or progressive pulmonary disease. While PFTs and HRCT provide complementary information on pulmonary function and structure and should ideally be performed in parallel, this study was specifically designed to determine which modality better detects longitudinal changes during follow-up in patients with CF in Indian population[11-13]. In India, there are no nationally standardized imaging guidelines for CF, and medical practitioners largely rely on recommendations from the European Cystic Fibrosis Society and the United States Cystic Fibrosis Foundation for patient management. In the absence of India-specific standardized guidelines, this study assumes importance and the evidence generated herein may support the development of suitable imaging strategies tailored to the Indian patient population.

The present study aims to perform a comparative analysis of HRCT and PFT, with the objective of determining their relative effectiveness in assessing the progression of lung disease in CF.

MATERIALS AND METHODS

The study was conducted at the Departments of Radiodiagnosis and Imaging, Sher-i-Kashmir Institute of Medical Sciences, and Government Medical College, Srinagar, Jammu and Kashmir in collaboration with the Departments of Pediatrics and Clinical Biochemistry.

Inclusion criteria were: Children diagnosed with CF based on characteristic clinical features, confirmed by sweat chloride testing and/or genetic analysis; age above 4 years; and the ability to perform reproducible PFTs. Exclusion criteria included age below 4 years and inability to perform reproducible PFTs.

Following diagnosis, patients underwent baseline PFTs and HRCT of the chest. Follow-up assessments were conducted after 12 months, including repeat PFTs and HRCT. Several HRCT-based scoring systems have been developed to quantitatively assess the degree of structural lung damage in CF, including the Brody, Helbich, Santamaria, Bhalla, and Oikonomou scoring systems. In the present study, we employed the Bhalla scoring system, as it is one of the most widely accepted and commonly used methods for quantitatively evaluating lung damage in patients with CF[14-16]. Bhalla computed tomography (CT) scores were compared with changes in pulmonary function, and statistical correlation was performed to evaluate the relationship between structural lung abnormalities and functional impairment.

CT protocol

All CT examinations were performed using a multi-detector CT scanner, 64-slice SOMATOM Sensation scanner (Siemens, Erlangen, Germany) with pediatric dose-optimized settings. The HRCT protocol involved sequential acquisition with a collimation of 2 mm × 1 mm. Tube voltage was adjusted according to patient size, typically ranging from 80-100 kVp, with automatic tube current modulation used to minimize radiation exposure.

Acquisitions were performed at a slice thickness of 1.0 mm at 10-mm intervals during deep suspended inspiration in cooperative children, whereas, free-breathing techniques were used in uncooperative patients. Prior to scanning, participants were trained in the proper technique of breath-holding to ensure optimal image quality. Image reconstruction was performed using a high spatial frequency algorithm (lung kernel) to enhance visualization of fine pulmonary structures. The scan range was limited to the thorax to further minimise radiation dose.

CT scoring

Structural lung abnormalities were assessed using the Bhalla scoring system (Table 1). Three experienced radiologists independently reviewed all images and then reached a consensus for each parameter, resulting in a single, consolidated score for every evaluated feature, which was subsequently summed to generate the final overall score for each patient.

Table 1 Bhalla scoring.

Category	Score
	0	1	2	3
Severity of bronchiectasis	Absent	Mild (luminal diameter slightly greater than diameter of adjacent blood vessel)	Moderate (lumen 2-3 times the diameter of the vessel)	Severe (lumen > 3 times diameter of vessel)
Peribronchial thickening	Absent	Mild (wall thickness equal to diameter of adjacent vessel)	Moderate (wall thickness greater than and up to twice the diameter of adjacent vessel)	Severe (wall thickness > 2 times the diameter of adjacent vessel)
Extent of bronchiectasis (No. of lung segments)	Absent	1-5	6-9	> 9
Extent of mucus plugging (No. of lung segments)	Absent	1-5	6-9	> 9
Sacculations or abscesses (No. of lung segments)	Absent	1-5	6-9	> 9
Generations of bronchial divisions involved (bronchiectasis or plugging)	Absent	Up to 4th generation	Up to 5th generation	Up to the 6th generation and distal
No. of bullae	Absent	Unilateral (not > 4)	Bilateral (not > 4)	> 4
Emphysema (No. of lung segments)	Absent	1-5	> 5
Collapse or consolidation	Absent	Subsegmental	Segmental or lobar

PFT protocol

Spirometry was performed using the EasyOne™ diagnostic spirometer (ndd Medizintechnik AG, Zurich, Switzerland), which meets and exceeds American Thoracic Society (ATS) standards for accuracy and precision. Testing was conducted in accordance with the 2005 ATS guidelines. Key spirometric parameters, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio, were recorded.

Statistical analysis

Statistical analyses were performed using Python 3.13.0. Continuous variables were expressed as mean ± SD. Paired comparisons between baseline and follow-up HRCT scores, as well as baseline and follow-up PFT parameters, were performed using a two-tailed paired t-test. As measurements were obtained from the same patients at two time points, this test was used to assess within-subject changes and to identify parameters showing statistically significant changes over the follow-up period. A two-tailed P value of < 0.05 was considered statistically significant. Pearson correlation coefficient (r) was used to evaluate the relationship between HRCT scores and spirometric parameters at each individual time point (baseline and follow-up). A P-value < 0.05 was considered statistically significant.

RESULTS

The present study enrolled 32 pediatric patients on an outpatient basis, with a mean age of 86.33 months (range: 48-192 months). The cohort comprised 14 males and 18 females. Although modest, the sample size is comparable to previously published studies in this domain. Notably, many other studies on this topic also had a modest number of patients[15,17].

HRCT at baseline demonstrated a spectrum of morphological pulmonary abnormalities. At baseline HRCT evaluation, bronchiectasis was the most common finding, present in 93.7% of patients, followed by peribronchial thickening (62.5%) and consolidation or collapse (50%) (Figure 1). Mucous plugging was observed in 31.3% of patients, while sacculation or abscess formation, bullae formation, and emphysema were each present in 15.6% of cases (Table 2). After one-year follow-up, there was a marked increase in the prevalence of most HRCT abnormalities. Bronchiectasis was observed in 96.9% of patients, and peribronchial thickening was present in all patients. Consolidation or collapse increased to 93.75%, while mucous plugging was noted in 62.5% of patients. Sacculation or abscess formation, bullae formation, and emphysema were seen in 25%, 37.5%, and 43.75% of patients, respectively, indicating radiological progression over the follow-up period (Table 2). The HRCT Bhalla score increased significantly from 5.5 ± 3.26 to 8.25 ± 3.82, corresponding to a 50% increase (paired t = 6.76, P < 0.0001), reflecting a marked progression of structural lung disease over the follow-up period (Table 2).

Figure 1 Depicting progressive deterioration of the lungs on high-resolution computed tomography. A: Baseline high-resolution computed tomography (HRCT) shows bronchial wall thickening with subsegmental collapse of the anterior segment of the left upper lobe, along with small centrilobular nodules; B: Follow-up HRCT after one year demonstrates extensive cylindrical, varicoid, and cystic bronchiectasis involving both lungs, with associated bronchial wall thickening and multiple air-space nodules.

Table 2 Comparison of high-resolution computed tomography chest findings at baseline and after one year of follow-up, n (%).

HRCT finding	Baseline (n = 32)	After 1-year follow-up (n = 32)
Bronchiectasis	30 (93.7)	31 (96.9)
Peribronchial thickening	20 (62.5)	32 (100)
Consolidation/collapse	16 (50)	30 (93.75)
Mucous plugging	10 (31.3)	20 (62.5)
Sacculation/abscess formation	5 (15.6)	8 (25)
Bullae formation	5 (15.6)	12 (37.5)
Emphysema	5 (15.6)	14 (43.75)

HRCT: High-resolution computed tomography.

The pulmonary function parameters showed a decline at one-year follow-up compared with baseline; however, none of the changes reached statistical significance. Mean FEV₁ decreased from 73.3 ± 19.4 at baseline to 69.5 ± 18.8 at follow-up, representing a 5.2% decrease (paired t = 1.73, P = 0.093). FVC declined from 78.7 ± 15.7 to 75.9 ± 15.6, corresponding to a 3.6% decrease (paired t = 1.60, P = 0.12). The FEV1/FVC ratio also decreased from 91.56 ± 12.6 to 88.94 ± 12.3, a 2.9% reduction (paired t = 1.70, P = 0.10). These findings suggest a trend toward declining lung function over time, although the changes were not statistically significant at one year (Table 3).

Table 3 Baseline and one-year follow-up high-resolution computed tomography (Bhalla) scores and pulmonary function tests, mean ± SD.

Parameter	Baseline	After 1-year follow-up	Age change (%)	P value
HRCT Bhalla score	5.50 ± 3.26	8.25 ± 3.82	50	< 0.001
FEV1 (% predicted)	73.38 ± 19.49	69.50 ± 18.81	5.2	0.093
FVC (% predicted)	78.75 ± 15.77	75.94 ± 15.6	3.6	0.12
FEV1/FVC	91.56 ± 12.62	88.94 ± 12.36	2.9	0.10

HRCT: High-resolution computed tomography; FEV1: Forced expiratory volume in one second; FVC: Forced vital capacity.

In contrast, the HRCT Bhalla score exhibited a marked increase of 50% over the same duration, reflecting a substantially greater worsening of structural lung disease compared with the relatively stable pulmonary function over the same period.

The correlation analysis demonstrated a moderate to strong negative association between PFT measures and HRCT scores. At baseline, the HRCT Bhalla score showed a significant negative correlation with both FEV1 and FVC, indicating that higher radiological disease severity was associated with poorer pulmonary function. This relationship was stronger for FEV1 (r = -0.67) than for FVC (r = -0.54) (Table 4). At one-year follow-up, the negative correlation between Bhalla score and pulmonary function became more pronounced. FEV1 demonstrated a very strong inverse correlation with Bhalla score (r = -0.79), while FVC also showed a strong negative correlation (r = -0.69), both of which were highly statistically significant. Overall, these findings suggest that as structural lung disease worsens over time, there is a corresponding decline in pulmonary function, particularly in airflow-related measures (Table 4).

Table 4 Correlation between high-resolution computed tomography (Bhalla) score and pulmonary function tests at baseline and one-year follow-up.

Time point	PFT parameter	Correlation with Bhalla score (r)	P value
Baseline	FEV1 (% predicted)	-0.67	0.002
	FVC (% predicted)	-0.54	0.019
Oneyear follow-up	FEV1 (% predicted)	-0.79	< 0.001
	FVC (% predicted)	-0.69	0.003

HRCT: High-resolution computed tomography; FEV1: Forced expiratory volume in one second; FVC: Forced vital capacity.

DISCUSSION

Advances in flexible bronchoscopy and HRCT have substantially enhanced our understanding of early lung injury in infants and preschool-aged children with CF. Bronchoalveolar lavage enables the detection of early neutrophilic airway inflammation, while HRCT has demonstrated high sensitivity in identifying structural lung abnormalities even in the absence of clinical symptoms. Among the earliest and most commonly reported radiological findings in CF are bronchial wall thickening and air trapping. In a landmark series of studies conducted by the Australian AREST-CF group, approximately 45% of infants with CF demonstrated bronchial wall thickening and nearly 66% showed evidence of air trapping at three months of age following newborn screening, despite the majority exhibiting no overt pulmonary manifestations at the time of evaluation[18,19].

In the present study, progression of structural lung disease, as assessed by the HRCT Bhalla score, was more pronounced than the decline observed in PFT parameters over the one-year follow-up period. While FEV1, FVC, and the FEV1/FVC ratio demonstrated only modest and statistically non-significant reductions (2.9%-5.2%), the Bhalla score showed a significant 50% increase (P < 0.0001). This discrepancy suggests that structural lung abnormalities may progress before measurable changes become evident in conventional spirometric indices, underscoring the higher sensitivity of HRCT in detecting early or subclinical disease progression. The absence of corresponding deterioration in PFT parameters despite worsening structural abnormalities on HRCT may be explained by several factors. First, PFT performance is highly dependent on patient cooperation, which can be suboptimal in young children, thereby limiting the ability of spirometry to detect subtle functional decline. In contrast, HRCT assessment remains feasible despite minor motion artifacts or variations in lung inflation and inspiratory effort. Second, PFT results are expressed as percentages relative to predicted reference values derived from population-based norms, introducing variability related to growth and developmental changes in children. Finally, HRCT provides superior visualization of localized pulmonary abnormalities, including atelectasis, bronchiectasis, and consolidation, whereas PFTs offer only a global assessment of airway and lung function. Collectively, these factors likely account for the greater sensitivity of HRCT in identifying early and progressive structural lung changes in CF during short-term follow-up. Given the inherently progressive nature of CF–related pulmonary disease, these findings suggest that HRCT may serve as a more sensitive modality than PFTs for monitoring disease progression. The results further highlight the importance of incorporating HRCT into longitudinal surveillance strategies to facilitate early detection of structural deterioration and enable timely therapeutic intervention.

While HRCT demonstrated greater sensitivity in detecting progressive structural lung changes compared with PFT parameters, this should not be interpreted as functional testing being less important. PFTs remain essential for assessing the global impact of disease on lung function in addition to its role in assessment of clinical severity, and treatment response. Rather than being competing modalities, HRCT and PFTs provide complementary information, with imaging reflecting structural abnormalities and spirometry reflecting overall lung function.

These findings align with previous studies from Europe reporting that HRCT can reveal ongoing lung damage even when spirometry remains relatively stable[20].

In addition, the study demonstrated that the extent and severity of bronchiectasis worsened significantly over the one-year follow-up. Notably, none of the patients with bronchiectasis identified on baseline HRCT showed resolution on follow-up imaging, indirectly supporting the concept that bronchiectasis is an irreversible pathological process. Consequently, patients with bronchiectasis at baseline are likely to demonstrate persistent bronchiectasis on subsequent imaging studies.

The divergence observed between radiologic progression and PFT stability emphasizes a clinically relevant “silent window” during which structural deterioration occurs without measurable functional loss-an interval that has significant implications for therapeutic escalation, antibiotic stewardship, and timing of airway-clearance interventions.

Although dose-optimization strategies were employed in the present study, the cumulative radiation exposure associated with repeated HRCT scans in children remains a vital consideration. There is a need for judicious use of CT, strict adherence to low-dose protocols, and exploration of alternative radiation-free imaging modalities such as lung magnetic resonance imaging (MRI), which is increasingly being investigated for longitudinal monitoring of pediatric CF.

Recently, the “iMAging managEment of cySTic fibROsis” consortium comprising of 21 pulmonologists and radiologists from Europe concluded that there is a need to establish clear guidelines for imaging in CF. The committee emphasized that these guidelines should precisely define the appropriate imaging modality, as well as its timing and frequency, according to specific clinical scenarios. These recommendations should take into account the patient’s age, severity of lung disease, and type of treatment[21]. The committee concluded that both CT and MRI should be used routinely and interchangeably to monitor the progression of lung disease in patients with CF. However, as CT imaging is currently more advanced in terms of validation and quantitative assessment, there is a particular need for harmonization of CT protocols. Such standardization is essential to minimize radiation exposure, especially in light of the significantly increased life expectancy now observed in patients with CF. MRI protocols also require harmonization and appropriate tailoring to meet the specific needs of patients with CF[21].

The European Cystic Fibrosis Society-Clinical Trials Network recently in 2025 issued recommendations for the use of chest CT scans to monitor lung disease progression in individuals with CF. These guidance statements were developed through a three-stage process: First, key questions were gathered via an anonymous online survey; second, an extensive literature review was conducted; and finally, a Delphi consensus procedure was completed. The guidance advises the use of ultra-low-dose CT scans, with an effective radiation dose of approximately 0.08 mSv (equivalent to 2-4 standard chest X-rays) for detection of structural lung charges and subsequent monitoring[22].

Various low-dose and ultra-low-dose CT protocols have been developed for the assessment of lung disease in CF. In addition, MRI is emerging as a valuable radiation-free imaging modality for evaluating lung damage in patients with CF[23-25]. However, its use is currently limited to specialized centers.

This study has several limitations. First, it represents a single-center experience with a limited number of patients. Another key limitation of the present study is the relatively short follow-up duration of one year. CF is a chronic, slowly progressive disease, and functional decline assessed by PFTs may lag behind structural abnormalities detected on imaging. The observed dissociation between radiological progression and relatively stable spirometric parameters may therefore reflect the temporal delay between structural damage and measurable functional impairment. Longer longitudinal follow-up is required to determine when progressive imaging abnormalities translate into clinically significant functional decline. Finally, interobserver variability was not formally evaluated, as Bhalla scores were determined through consensus interpretation by three experienced radiologists.

Future multicentric studies involving a larger cohort and prolonged longitudinal imaging follow-up are necessary to better understand the disease trajectory and to further refine and standardize management guidelines. Additionally, the use of low-dose CT protocols is essential to minimize radiation exposure, particularly in the pediatric population.

CONCLUSION

Despite significant radiological worsening of structural lung changes detected by HRCT, only minimal and statistically non-significant changes were observed in pulmonary function indices as assessed by PFTs. These findings suggest that PFTs may be less sensitive in detecting ongoing overall lung damage in CF. This underscores the importance of HRCT as a sensitive tool for the early detection and monitoring of radiological disease progression, thereby enabling timely institution of therapeutic measures to halt or slow the progression of lung disease.