Therapeutic interventions and pulmonary function in pediatric patients with post-infectious bronchiolitis obliterans

Abstract

Post-infectious bronchiolitis obliterans (PIBO) is a rare chronic obstructive pulmonary disease affecting children after a severe respiratory infection. The primary goal of this narrative review is to synthesize evidence on pulmonary function in children with PIBO, with a focus on spirometric indices, and to evaluate the efficacy of therapies reported in the literature. It also provides an overview of the disease’s epidemiology, risk factors, clinical presentation and diagnostic methods. Studies reported various spirometric parameters including forced expiratory volume in one second, forced vital capacity, the ratio between these two parameters, and forced expiratory flow at 25%-75%. A narrative synthesis described therapies including bronchodilators, corticosteroids, macrolides, combination regimens, novel therapies and non-pharmacological interventions. Most studies were small, but data showed moderate to severe impairments in pulmonary function in pediatric PIBO, with mild heterogeneity. Corticosteroids and combined therapies offered short-term relief, but long-term benefits were limited by adverse effects. Pulmonary rehabilitation may preserve lung function and quality of life, although evidence remains scarce. Given the limited research on therapy and pulmonary outcomes, further studies are necessary to understand the long-term effects of treatments. This review underscores the urgent need for multicenter studies and evidence-based guidelines to improve care for children with PIBO.

Key Words: Post-infectious bronchiolitis obliterans; Pediatric pulmonary function; Children; Therapeutic interventions; Spirometric monitoring

Core Tip: Post-infectious bronchiolitis obliterans leads to permanent small-airway obstruction and significant spirometric deficits in children, notably reduced forced expiratory volume in one second and forced expiratory flow at 25%-75% with poor bronchodilator response, while diffusing capacity of the lung for carbon monoxide often remains normal. This narrative review links these pulmonary function parameters with therapeutic interventions, showing that early use of inhaled or systemic corticosteroids and macrolides can stabilize or modestly improve lung function. Emerging combination regimens, such as fluticasone-azithromycin-montelukast, show promise but need further validation. Integrating regular spirometric monitoring with tailored anti-inflammatory strategies may optimize clinical outcomes and underlines the need for prospective studies.

INTRODUCTION

The term bronchiolitis obliterans (BO) includes a group of diseases with different characteristics. There is no universally accepted definition for this condition. BO refers to a heterogeneous group of diseases characterized by persistent airway obstruction due to small airway involvement, often showing poor response to bronchodilator treatment[1]. Among its forms, post-infectious bronchiolitis obliterans (PIBO) is a rare but severe chronic lung disease that can develop after a lower respiratory tract infection in childhood, commonly caused by adenovirus, respiratory syncytial virus (RSV), or measles, especially in children under two years of age. BO is characterized by persistent airway obstruction with radiological and functional evidence of small airway involvement and poor response to bronchodilator treatment[1]. The pathogenesis involves bronchiolar epithelial injury, followed by an inflammatory reaction and progressive fibrotic remodeling that leads to irreversible luminal obliteration[1,2]. Clinically, PIBO presents with persistent cough, wheezing, dyspnea, and progressive decline in pulmonary function parameters such as forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC). Due to the chronic and progressive nature of PIBO, therapies focus on managing inflammation, reducing symptoms, and preserving lung function. Treatment approaches range from corticosteroids, macrolides, bronchodilators and combined therapies. The efficacy of these therapies is often assessed through pulmonary function tests (PFTs), particularly spirometry, which provides objective measures of airway obstruction and lung capacity. Previous studies on the pulmonary function parameters in children affected by PIBO demonstrated a variable range of impairment due to differences in the characteristics of the study population and the degree and age of respiratory insults[3-5].

Although corticosteroids, macrolides, bronchodilators, and combination regimens are commonly used, current therapeutic approaches are largely empirical and often based on small observational studies with heterogeneous populations. There is still no universally accepted diagnostic definition, and evidence-based guidelines to standardize treatment pathways for this condition are lacking. Furthermore, available studies often include small pediatric cohorts with short follow-up, and data on long-term pulmonary function trajectories and quality of life are limited.

This review aims to critically evaluate the existing evidence on therapeutic interventions for children with PIBO and their impact on pulmonary function outcomes, highlighting the need for standardized diagnostic criteria, larger multicenter studies, and clear clinical guidelines to improve care for this condition.

EPIDEMIOLOGY

PIBO is a rare but severe chronic lung disease in children, with its true incidence likely underestimated due to diagnostic challenges and variability in clinical presentation. It most commonly affects previously healthy children under the age of three. Epidemiological studies suggest that PIBO is more prevalent in developing countries, where access to timely and advanced medical care for severe respiratory infections may be limited. It is also more frequent among Argentinians, Native Americans, and native Koreans, highlighting the key role of specific genetic factors in initiating or perpetuating the pathological process[1,6,7]. Although specific population-based incidence rates are lacking, hospital-based studies report that PIBO occurs in a small percentage of children hospitalized for viral pneumonia.

PATHOPHYSIOLOGY AND RISK FACTORS

The pathogenesis of PIBO in children is thought to result from an exaggerated and prolonged inflammatory response after a severe lower respiratory tract infection, which leads to chronic and often irreversible damage to the small airways[2]. The bronchiolar epithelial damage following lower respiratory tract infections leads to progressive epithelial dysfunction, inflammation and fibrotic remodeling, hallmarks of PIBO[2]. While it is widely accepted that bronchiolar epithelial injury triggers inflammation and fibrotic remodeling, the exact mechanisms driving persistent inflammation and incomplete resolution remain unclear, and different studies have highlighted conflicting findings regarding the role of immune dysregulation and genetic susceptibility. Adenovirus (particularly types 3, 7, and 21) is reported as the most common causative agent in severe cases, although other pathogens like influenza virus, RSV, parainfluenza virus, and Mycoplasma pneumoniae have also been involved[1]. However, the relative contribution of each pathogen remains debated, as some studies suggest that host factors — including genetic polymorphisms, prematurity, or pre-existing airway anomalies — may play an equally critical role in determining who develops PIBO after infection. This condition does not appear to have a strong gender predilection, though some studies have reported a slight male predominance. Environmental exposures, such as tobacco smoke or air pollution, and factors like mechanical ventilation or prolonged hospitalization, have been variably associated with increased risk, but their independent impact is still uncertain and likely multifactorial[1,8]. Overall, while the general pathophysiological framework is recognized, the heterogeneity of clinical presentations and the lack of robust prospective studies leave important questions open about why only some children develop persistent airway obliteration and how to best identify those at risk.

CLINICAL PRESENTATION

Children with PIBO typically present with persistent respiratory symptoms that do not fully resolve following an acute lower respiratory tract infection, often of viral origin (Figure 1). The hallmark symptoms include chronic cough, exertional dyspnea, wheezing, and recurrent respiratory infections, but these features are non-specific and can overlap with other chronic airway diseases. Notably, while wheezing and rhonchi on auscultation are common, they are not pathognomonic, and physical examination alone is often inconclusive for diagnosis. Some children may show signs of chest hyperinflation or growth delay, but these findings vary widely among studies, reflecting both the heterogeneity of the disease and differences in diagnostic criteria used in the literature. Another point of debate is the natural history of PIBO: Some authors describe a relatively stable course with slow lung function decline, whereas others report progressive deterioration and significant impairment in daily activities and quality of life. These discrepancies may stem from differences in patient populations, follow-up duration, and lack of standardized definitions. Altogether, the clinical picture of PIBO remains unclear due to the heterogeneous presentation of the disease.

Figure 1  Chest X-ray showing right upper and middle lobe consolidation in a patient with adenoviral pneumonia who later developed post-infectious bronchiolitis obliterans.

DIAGNOSIS

The diagnosis of PIBO in children is primarily clinical, based on persistent respiratory symptoms, and is supported by complementary findings from imaging and pulmonary function tests[2]. Histopathology through lung biopsy is still considered the gold standard for definitive diagnosis, as it provides direct evidence of bronchiolar obliteration and fibrosis. However, its invasive nature, risk of complications, and limited feasibility in young children make it rarely performed in routine practice. Moreover, sampling errors and patchy disease distribution can limit its diagnostic yield. PFTs play a supportive role[2]. However, spirometry requires good patient cooperation; in younger children, this limits its applicability. Alternative methods like impulse oscillometry or plethysmography can assess airway resistance and lung volumes but may require sedation. Furthermore, in early disease stages, PFTs may appear normal, which can delay diagnosis.

Computed tomography findings

High-resolution computed tomography (HRCT) of the chest is currently the most informative non-invasive tool, revealing typical features such as mosaic attenuation, air trapping, bronchial wall thickening, and hyperinflation, especially on expiratory scans[1] (Figure 2). Nevertheless, the interpretation of these patterns can be subjective, and there is no consensus on standardized computed tomography (CT) criteria for PIBO in children. Importantly, while HRCT is highly sensitive for detecting air trapping and mosaic attenuation, its specificity is lower since similar patterns may be observed in other chronic airway diseases. Previous studies demonstrate that performing inspiratory CT only will miss some cases of bronchiolitis obliterans and that adding in expiratory sections improves sensitivity[9,10]. In young children (under 6 years), performing reliable inspiratory and expiratory scans often requires general anesthesia, although advances in ultra-fast scanning have reduced this need by minimizing motion artifacts. The radiation exposure from chest CT remains a concern, especially for repeated imaging in the pediatric population. Despite technological improvements reducing doses to below 1 mSv per scan, cumulative exposure should always be weighed against diagnostic benefit. The use of intravenous contrast is generally not required for PIBO diagnosis but may help in differential diagnosis or pre-transplant assessment.

Figure 2 Chest high-resolution computed tomography scan of a patient with post-infectious bronchiolitis obliterans post adenovirus showing middle lobe atelectasis with air bronchogram and bronchiectasis. Diffuse mosaic pattern and air trapping.

Chest X-ray, while easily accessible, has limited sensitivity and specificity for PIBO and may only show non-specific signs such as hyperinflation or atelectasis (Figure 1). Therefore, it should not be relied upon alone to exclude or confirm the diagnosis.

Laboratory tests are non-specific and mainly serve to rule out other conditions, as there are no validated biomarkers for PIBO.

Overall, each diagnostic tool has significant limitations: Lung biopsy is invasive and impractical; PFTs are age-restricted and may be normal early on; HRCT, while informative, carries radiation risks and requires cooperation or sedation in younger children. These challenges highlight the need for a multidisciplinary approach, involving pediatric pulmonologists, radiologists, and infectious disease specialists, to integrate clinical, radiologic, and functional data for accurate diagnosis and to minimize misclassification.

Comment on imaging: The combination of chest X-ray (Figure 1) and HRCT (Figure 2) illustrates how initial pneumonia-related consolidations can evolve into structural changes typical of PIBO, such as mosaic perfusion and bronchiectasis. However, radiologic patterns alone should always be interpreted in the context of clinical history and pulmonary function results, given their limited specificity.

PULMONARY FUNCTION

Pulmonary function assessment is essential in the follow-up of children with PIBO, but its role in the initial diagnosis is limited by practical and technical challenges. Spirometry, when feasible — usually in cooperative children older than 5-6 years — typically shows small airway involvement[3]. However, it is important to recognize that spirometry may be normal in early stages or in mild cases, and its sensitivity depends heavily on the child’s ability to perform reliable maneuvers. In younger children unable to undergo conventional spirometry, alternative techniques such as impulse oscillometry (IOS) and plethysmography can offer indirect information on airway resistance and lung volumes. Yet, these methods are not routinely available in all pediatric centers, require sedation in some cases, and still lack universally accepted pediatric normative data, which limits their widespread use and standardization. Moreover, interpreting IOS results in PIBO can be challenging due to overlapping findings with other obstructive airway diseases.

Body plethysmography, where available, may reveal lung hyperinflation and increased residual volume (RV) and total lung capacity (TLC), suggesting air trapping and small airway involvement[1,6]. However, the application of pulmonary function testing in young children remains challenging due to cooperation issues, and age-appropriate normative data are limited[1,4] (Table 1).

Table 1 Pulmonary function techniques in pediatric post-infectious bronchiolitis obliterans: Practical comparison.

Technique	Recommended age	Advantages	Limitations	Role in PIBO
Spirometry	> 5-6 years (cooperative)	Widely available; standard obstructive pattern; non-invasive	Not feasible in very young children; variable sensitivity in early/mild disease	Useful to detect irreversible obstruction and monitor over time
Impulse oscillometry	3-6 years (or older)	Minimal cooperation; measures small airway resistance	Limited availability; lack of standard pediatric reference ranges; interpretation may vary	Helpful in uncooperative children but not diagnostic alone
Body plethysmography	> 5-6 years (cooperative)	Detects air trapping; measures lung volumes (RV, TLC)	Requires full cooperation; not always available; sometimes sedation needed	Supports diagnosis of air trapping; complements spirometry
DLCO	> 7-8 years (good technique needed)	Assesses alveolar-capillary integrity; typically preserved in PIBO	Technically demanding; requires good breath-hold and cooperation; limited use in young children	Helps distinguish PIBO from interstitial diseases

PIBO: Post-infectious bronchiolitis obliterans; RV: Residual volume; TLC: Total lung capacity; DLCO: Diffusing capacity of the lung for carbon monoxide.

Measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) can be informative: In PIBO, DLCO is generally preserved because the primary injury involves the conducting airways rather than the alveolar-capillary interface[2]. This helps differentiate PIBO from interstitial lung diseases where DLCO is typically reduced. Still, DLCO testing also relies on good patient technique and is feasible only in older, cooperative children.

Overall, pulmonary function tests provide supportive but not definitive information. They have limited sensitivity in early disease stages, require age-appropriate cooperation or specialized equipment under sedation, and cannot distinguish PIBO from other causes of fixed airway obstruction without supportive clinical and imaging findings.

Therefore, while abnormal spirometry and lung volumes can strengthen the suspicion of PIBO, they must always be interpreted together with clinical history and imaging results to avoid misdiagnosis. Over time, lung function may remain stable, deteriorate, or show minor improvements depending on the severity of the initial insult and ongoing inflammation[3,4]. Regular longitudinal pulmonary function monitoring remains essential to assess disease progression, evaluate response to therapy, and identify candidates who may benefit from advanced interventions.

Spirometry

Spirometry generally shows an obstructive pattern involving the small airways. However, in the early stages of the disease, pulmonary function tests may appear normal, while in later stages, a typical pattern can be observed. The spirometric pattern usually reveals a fixed or irreversible obstruction on the flow- volume curve, with a reduction in FEV₁, the Tiffeneau index (FEV₁/FVC) and end-expiratory flow (MEF25) and elevated RV/TLC[1]. There is usually a poor response to bronchodilators, reflecting the fixed nature of the small airways narrowing[2]. Additionally, forced expiratory flow between 25% and 75% of the pulmonary volume (FEF25%-75%) is frequently decreased, further highlighting small airway involvement[3]. Nevertheless, reliable spirometry requires patient cooperation, so it is usually feasible only in children over five or six years of age[1]. In younger patients, this can limit its diagnostic utility, and early disease stages may yield normal results, potentially delaying diagnosis[3,7]. Longitudinal cohort studies confirm that severe impairment can persist for years, underscoring the importance of repeated testing to monitor functional decline and guide therapy[3]. Despite these strengths, spirometry remains effort-dependent and less sensitive for detecting early small airway changes[6].

DLCO

In children with (PIBO), the preserved DLCO represents a key functional parameter. Cazzato et al[2] reported that while FEV₁ and FEF25%-75% decline progressively over time due to airway fibrosis, DLCO values frequently result within normal ranges, suggesting that alveolar-capillary gas exchange remains unchanged. This finding aligns with the workshop report led by Jerkic et al[1], which underscores that PIBO is characterized by obstruction of the small airways, with sparing of alveolar structures- thus explaining the typically normal DLCO results in these patients[2]. DLCO values typically remain normal, reinforcing the concept that PIBO primarily affects conducting airways rather than alveolar structures. This emphasizes the importance of including DLCO measurement in the diagnostic and follow-up of PIBO, offering valuable insight into the characteristics of lung injury.

Body plethysmography

Body plethysmography can provide additional insight into lung volumes such as RV and TLC. In PIBO, these often reveal hyperinflation and air trapping, particularly when spirometry is inconclusive[1,2,6]. This technique may be useful to detect peripheral airway involvement, which is typical in PIBO but harder to assess with spirometry alone. However, like other functional tests, it requires good cooperation and is usually feasible only in children older than 6-7 years. Younger or non-cooperative children may need sedation, which limits its routine application. Furthermore, there are few standardized reference values for pediatric PIBO patients, highlighting the need for standardized protocols and multicenter data to confirm its diagnostic and prognostic value[1,6].

Overall, while these functional assessments remain fundamental tools in the diagnostic work-up of PIBO, the available evidence suffers from significant heterogeneity between studies, small sample sizes, and a lack of standardized long-term follow-up. This limits the strength of recommendations and underscores the need for collaborative research to better define diagnostic thresholds and prognostic trajectories[1,4,8].

THERAPEUTIC INTERVENTIONS

The treatment of PIBO is empirical. Therapy for this condition includes pharmacological and supportive treatments combined with non-pharmacological interventions[11,12] (Table 2). The goal of treatment is to limit inflammation by inhibiting lymphocytic proliferation. Generally, before initiating systemic anti-inflammatory therapy, it is advisable to perform a bronchoscopy with BAL to investigate any persistent infections.

Table 2 Summary table of treatment options.

Treatment option	Description	Comments/evidence
Corticosteroids	Systemic or inhaled steroids used to reduce inflammation	Often used during acute exacerbations; long-term benefits uncertain; some improvement in symptoms reported
Bronchodilators	Inhaled β2-agonists and anticholinergics to relieve airway obstruction	Symptomatic relief, but variable response due to fixed airway obstruction
Macrolide antibiotics	Anti-inflammatory and immunomodulatory properties (e.g., azithromycin)	May reduce inflammation; some evidence in other chronic airway diseases; limited data in PIBO
Immunosuppressants	Agents like azathioprine, cyclophosphamide, or mycophenolate mofetil in severe cases	Used in refractory disease; evidence limited; risks of immunosuppression must be balanced
Oxygen therapy	Supplemental oxygen for hypoxemia	Supportive care in advanced disease with chronic hypoxia
Pulmonary rehabilitation	Exercise training, airway clearance, and breathing techniques	Improves quality of life and functional status; standard supportive care
Lung transplantation	Considered in end-stage PIBO with respiratory failure	Rare; only for selected severe cases; long-term outcomes variable
Other therapies	Experimental or adjunctive therapies, including antivirals, mucolytics, or novel agents	Limited evidence; research ongoing; no standard recommendations

PIBO: Post-infectious bronchiolitis obliterans.

Pharmacological therapies

Therapeutic interventions for PIBO in children aim to reduce inflammation, alleviate symptoms, and preserve lung function, although no universally effective treatments exist due to the irreversible nature of airway damage. Corticosteroids, both systemic and inhaled, are commonly used in the early stages or during disease exacerbations to suppress ongoing inflammation. Oral prednisolone or intravenous methylprednisolone pulse therapy may be considered in moderate to severe cases, especially if active inflammation is suspected. Immunosuppressive agents such as azithromycin (used for its anti-inflammatory properties), hydroxychloroquine, or methotrexate have been explored in selected cases with variable success, primarily in children with a progressive clinical course. Bronchodilators, including beta-agonists and anticholinergics, may provide symptomatic relief, although their effect on lung function is often limited due to fixed airway obstruction.

Previous studies[4,5,13] described the bronchodilator response as an increase in the FEV₁ by at least 12% following salbutamol inhalation. Other studies documented the prevalence of positive bronchodilator responses in pediatric patients ranging from 30% to 83.3%[2,13-15].

Steroids: Based on the clinical course of the disease, inhaled and systemic steroids are used to contrast the inflammatory component. Corticosteroids should be administered as early as possible after diagnosis, before airway fibrosis develops[16].

There is general consensus that the treatment of choice is intravenous steroid pulse therapy, using methylprednisolone at a dose of 10-30 mg/kg for three consecutive days, repeated monthly for a period of 3 to 6 months. This treatment regimen has proven effective in pediatric patients with interstitial lung disease[1]. Long-term oral systemic corticosteroid therapy should be avoided, as it is associated with undesirable side effects and serious complications such as infection-related mortality and bone fractures.

Previous studies have shown that children affected by PIBO may benefit from methylprednisolone pulse therapy if bronchial wall thinning is observed on pre-treatment chest CT[17].

Given the unclear long-term effects of corticosteroids, their toxicity, and the high risk of severe infections, it would be advisable to use a non-steroidal treatment for the long-term management of this disease.

Azithromycin: In contrast to steroid therapy, azithromycin treatment is known to be effective in controlling neutrophilic inflammation and in promoting the improvement of lung function in various diseases such as diffuse panbronchiolitis, cystic fibrosis, and post-transplant bronchiolitis obliterans syndrome (BOS)[18-20]. The exact mechanism by which azithromycin modulates the inflammatory response is still unclear. Different mechanisms have been described such as a reduction in neutrophil count in the airways, suppression of interleukin-8 and other neutrophil-chemotactic cytokines and interference with neutrophil function. Regarding the use of azithromycin in PIBO, the data in the literature are scarce. In any case, even though no randomized controlled trials exist in children with PIBO, oral azithromycin at a dose of 10 mg/kg three times per week is recommended, having demonstrated efficacy in other obstructive diseases[16].

Fluticasone, azithromycin, and montelukast: In initial trials, montelukast slowed FEV₁ decline in fibroproliferative BOS following lung transplantation[21], although a subsequent study by Ruttens et al. found no survival advantage over placebo[22]. However, several reports have indicated that combining inhaled fluticasone, azithromycin, and montelukast (FAM) may offer clinical and functional benefits in BOS patients[23]. A recent phase II, open-label, multicenter trial assessed FAM together with an initial corticosteroid pulse in new-onset BOS post-hematopoietic stem cell transplantation. The primary endpoint was a ≥ 10 % decline in FEV₁ at 3 months[24] (Table 3). Treatment failure occurred in only 6 % of the FAMtreated group vs 40 % in historical controls (P < 0.001), suggesting the regimen was well tolerated and potentially effective at halting pulmonary deterioration. Evidence for FAM in PIBO remains limited. There are only a few single-center case series describing its use in children.

Table 3 Proposed combination therapies for post-infectious bronchiolitis obliterans.

Ref.	Therapies	Pulmonary function outcomes	Key points/notes
Zheng et al[25] retrospective (2022) — 34 children, age > 5 years (n = 20); ≤ 5 years (n = 14)	Continuous vs intermittent ICS (budesonide ± terbutaline)	After 1-year, continuous ICS showed improvements in FVC, FEV1, MMEF 25%-75%, tidal flow ratios; intermittent ICS did not	Continuous ICS significantly improved airway obstruction; > 50% had positive bronchodilator tests
Zhang et al[26] (2018) Clinical cohort, China (2014-2017) — 30 children, median age 17 months	Long-term nebulized budesonide + terbutaline + ipratropium	Significant increase in TPEF%/TE and VPEF%/VE; HRCT improved in 82% of patients; symptoms greatly improved (P < 0.01)	Triple nebulization well tolerated, effective in young children, with both functional and radiologic improvements
Li et al[31] workshop report — 42 children	Oral prednisone (1.5 mg/kg/day taper over 6-9 months) + azithromycin (5-10 mg/kg, 3 days/week × 6 months)	Defined “effective”: Stable lung function (as < 10% decline); > 50% responded with reduced wheezing; effective in 86% of cases. No HRCT improvement	Combined steroids + azithromycin frequently effective; no control groups, but high subjective + functional response rates
Jerkic et al[1] Workshop report (BOS studies)	FAM regimen: Fluticasone + azithromycin + montelukast + steroid pulse	In BOS, poor pulmonary decline halted: Treatment failure (≥ 10% FEV1 drop) was only 6% at 3 months vs 40% historical controls	While untested in PIBO, single-center use suggested safety; efficacy needs formal trials
Yilmaz et al[27] (2023) IVIG study (2010-2021) — 11 severe PIBO patients	Regular IVIG infusions (weekly/monthly)	Reduced infections and hospital visits; all patients weaned off oxygen; radiological scores improved; BMI increased	Retrospective uncontrolled but showed clinical and radiologic gains in severe PIBO
Teixeira et al[28] (2013) randomized control trial — 30 patients	Tiotropium (LAMA) ± short-acting β2 agonists	Improvement in acute FEV1, FVC and FEF25%-75%; bronchodilator reversibility seen in approximately 25% of PIBO patients in related studies	Suggests LAMAs may be useful in PIBO—especially those with some reversibility

ICS: Inhaled corticosteroids; FVC: Forced vital capacity; HRCT: High-resolution computed tomography; FAM: Fluticasone, azithromycin, and montelukast; BMI: Body mass index; PIBO: Post-infectious bronchiolitis obliterans; LAMAs: Long-acting muscarinic antagonists.

Inhaled corticosteroids: A retrospective study that evaluates the effects of continuous inhaled corticosteroids (ICSs) on lung function in patients with PIBO in remission found that ICSs can effectively improve lung function and relieve airway obstruction in patients with PIBO > 5 years of age in remission, especially continuous ICSs (Table 3)[25]. After one year of ICSs therapy, patients over the age of 5 showed significant improvement in FVC and FEV₁ compared to the beginning of follow-up. Also triple nebulized therapy (budesonide + bronchodilators) in toddlers significantly improves small airway tidal flow and imaging (Table 3)[26].

Intravenous immunoglobulin: Intravenous immunoglobulin (IVIG) offers notable benefits in severe PIBO when first-line measures fail, improving oxygenation and reducing infections and hospital visits. As demonstrated in the study by Yilmaz et al[27], PIBO patients exhibited favorable clinical and radiological responses to regular IVIG therapy, potentially due to steroid-induced or underlying immune dysfunction in severe PIBO (Table 3).

Long-acting muscarinic antagonists: Long-acting muscarinic antagonists (LAMAs) show potential benefit, particularly in partially reversible PIBO, improving FEV₁. The trial conducted by Teixeira demonstrated a significant acute bronchodilator effect in children with post-infectious bronchiolitis obliterans (PIBO). In this randomized, double-blind, placebo-controlled crossover study involving 30 patients aged 6-16 years, a single 18 μg dose of tiotropium resulted in marked improvements in FEV₁, FVC, FEV₁/FVC, and FEF25%-75%, along with reduced air trapping and airway resistance, lasting up to 24 hours. These findings indicate that tiotropium may offer short-term functional benefits in PIBO, although its long-term efficacy remains unproven (Table 3)[1,28].

Non-pharmacological interventions

Supportive management of pediatric PIBO focuses on optimizing respiratory function, nutrition, immunity, and quality of life. Non-pharmacological interventions play a crucial role in the comprehensive management of PIBO. Supplemental oxygen is administered in case of hypoxemia especially during the first years of disease, with pulsed oximetry value below 92%[29]. Long-term oxygen therapy may be required in patients with chronic hypoxemia to support adequate tissue oxygenation and prevent complications such as pulmonary hypertension. Adequate nutritional support is essential to promote growth and respiratory muscle strength. Immunizations, specifically seasonal influenza and pneumococcal vaccines, are routinely recommended to prevent respiratory infections that could exacerbate disease. In patients with bronchiectasis, airway clearance via inhalation of hypertonic saline or physiotherapy can help mobilize secretions from the small airways. Finally, physical exercise and pulmonary rehabilitation are recommended components of chronic care. Pulmonary rehabilitation programs, including physical therapy and breathing exercises, help improve exercise tolerance, reduce symptoms, and enhance quality of life, but data are available only for patients with BOS. In end-stage or refractory cases with severely impaired lung function and poor quality of life, lung transplantation may be considered, although it remains a last resort due to its complexity and associated risks[29] (Table 4). The main purpose of treatment is tailored control for each patient according to lung damage and clinical response.

Table 4 Non-pharmacological interventions.

Intervention	Benefit	Limitations
Oxygen therapy	Corrects hypoxemia; prevents pulmonary hypertension[29]	Does not modify disease; burden of long-term use
Airway clearance	May reduce secretions in bronchiectasis	Extrapolated from BOS data; no PIBO-specific trials
Pulmonary rehabilitation	Improves exercise tolerance and quality of life in BOS	No pediatric PIBO data; resource-intensive
Nutrition vaccination	Supports growth and immunity	Standard of care, not disease-specific
Lung transplantation	Life-saving in end-stage disease	Early graft dysfunction, higher perioperative complications, low mortality rate; limited donor supply[32]

BOS: Bronchiolitis obliterans syndrome; PIBO: Post-infectious bronchiolitis obliterans.

Because no randomized, PIBO-specific trials exist, all current treatments for children remain empirical. The following hierarchy ranks interventions by pediatric evidence strength:

Critical summary: Strongest pediatric data support systemic steroid pulses, but evidence is limited to small (n < 50), uncontrolled series with short follow-up. ICS and azithromycin show promising safety and moderate efficacy in cohorts of 30-42 children, yet lack prospective randomization. Tiotropium and IVIG remain hypothesis-generating in small pediatric samples. Non-pharmacological measures are biologically plausible but untested in PIBO children.

Overall, establishment of a true therapeutic hierarchy in pediatric PIBO mandates multicenter, controlled trials, direct head-to-head comparisons, and extended follow-up to balance efficacy against toxicity and to develop evidence-based management guidelines.

DISCUSSION

This review evaluated the pulmonary function outcomes in pediatric PIBO and offered a descriptive overview of various therapeutic interventions. Our findings underline the difficulties in managing PIBO in children. Despite increasing awareness of pediatric PIBO, its management remains driven more by expert opinion than by strong evidence. Due to the rarity of the disease, the studies available are mostly retrospective, small-scale, and methodologically heterogeneous, and many are based on adult patients, which severely limits the strength of their conclusions. Functional impairments are well documented but based on small, retrospective cohorts. Cazzato et al[2] analyzed 10 children in a single-region cohort, confirming a predominantly obstructive pattern with significantly reduced FEV₁ and FEF25%-75% in the majority. However, these studies lack control groups, and follow-up duration varies widely, limiting conclusions about natural history or treatment effects. Similarly, Colom et al[3] followed 46 children for up to 12 years, noting that some patients demonstrate mild improvements in FEV₁ and FVC over time, but the lack of standardized interventions and possible survival bias constrain generalizability.

Radiological correlates and quantitative CT analysis have shown promise, as highlighted by Jung et al[4] and Kim et al[5] with cohorts of 47 and 23 children, respectively. Both studies emphasize the association between air trapping, mosaic perfusion, and worse pulmonary function. However, small sample sizes, retrospective designs, and lack of external validation reduce the reliability of proposed imaging biomarkers.

Several studies assessing bronchodilator responsiveness, such as Zheng et al[25] and Zhang et al[26], suggest that a variable percentage of patients may show partial reversibility. However, these reports combine patients with varying disease severity, stages, and treatment histories, confounding the interpretation. Moreover, the small sample sizes (e.g., Zhang et al[26], n = 30) and retrospective design heighten the risk of overestimating treatment effects due to regression to the mean or measurement variability. Longitudinal data show that pulmonary function may remain stable, decline, or slightly improve depending on the severity of initial damage and response to therapy[30] (Table 5).

Table 5 Key studies on post-infectious bronchiolitis obliterans: Sample sizes, main results, and critical limitations.

Ref.	Sample size (n)	Design	Main findings	Key limitations/biases
Jerkic et al[1]	(Multiple studies)	Retrospective, multicenter workshop summary	Provided diagnostic framework based on expert consensus; highlighted frequent severe obstructive patterns on PFTs and HRCT	Mainly expert opinion, heterogeneous cases, lack of standardized treatment comparisons
Cazzato et al[2]	10	Case series	Confirmed persistent airway obstruction; FEV1 and FEF25%-75% significantly reduced in most patients	Small cohort, no control group, variable follow-up, single-region recruitment
Colom et al[3]	46	Cross sectional (12-year follow-up)	Some children showed mild improvements in FEV1 and FVC over 12 years; severity depends on initial damage	Limited generalizability, possible survival bias, lack of treatment standardization
Jung et al[4]	47	Cross sectional	Identified predictors of poor prognosis (e.g., mosaic perfusion, air trapping on CT)	Short term follow-up, single-center, no external validation
Kim et al[5]	23	Cross-sectional with quantitative CT	Suggested quantitative CT correlates well with lung function	Variability in CT technique, no standard thresholds
Li et al[31]	42	Prospective observational	Azithromycin + corticosteroids improved symptoms in 86% of children	Non-randomized, no control group, subjective symptom assessment
Zheng et al[25]	34	Retrospective ICS comparison	Continuous inhaled corticosteroids improved FEV1 more than intermittent use in children > 5 years	Lack of randomization, possible adherence bias, short follow-up
Zhang et al[26]	30	Case series nebulization therapy	Long term budesonide + bronchodilator nebulization in toddlers improved small airway tidal flows and CT findings	Small cohort, no control group; subjective imaging interpretation; variable treatment duration
Teixeira et al[28]	30	Randomized control trial	Tiotropium showed acute bronchodilator response in some PIBO patients	Single center, short follow-up
Yilmaz et al[27]	11	Retrospective, single center	IVIG treatment showed clinical stability in severe PIBO	Small sample, no comparative arm, retrospective bias
Colom and Teper[30]	125	Retrospective observational study	Proposed criteria to diagnose PIBO early	Single center, retrospective design, limited generalizability, Needs validation in prospective cohorts
Rosewich et al[12]	20 (+ 22 controls)	Cross-sectional	Highlighted persistent neutrophilic airway inflammation	No intervention tested, only descriptive, single time-point, age variability

PFTs: Pulmonary function tests; HRCT: High-resolution computed tomography; FVC: Forced vital capacity; CT: Computed tomography; ICS: Inhaled corticosteroids; PIBO: Post-infectious bronchiolitis obliterans; IVIG: Intravenous immunoglobulin.

Corticosteroid treatment, the mainstay of therapy, is supported by limited evidence of variable quality. Lee et al[15] conducted a meta-analysis pooling small observational studies but acknowledged high heterogeneity (I² > 70%) and moderate to high risk of bias in most included studies. Similarly, Yoon et al[17] found that pulse methylprednisolone may improve lung function in selected patients, however their study had only 17 subjects and lacked randomization or placebo control. These design limitations weaken the validity of conclusions about optimal dosing, timing, or duration. Regarding macrolides, Li et al[31] described clinical benefit from azithromycin plus corticosteroids in 42 children but did not include a comparator arm, making it impossible to isolate the drug effect from the natural disease course (Table 6). While randomized controlled trials are lacking for pediatric patients, azithromycin is currently recommended at 10 mg/kg three times per week, based on its efficacy in related chronic airway diseases[16]. The FAM regimen (fluticasone, azithromycin, montelukast), initially trialed in BOS post-transplant, demonstrated a marked reduction in FEV₁ decline and treatment failure rates (6% vs 40% in historical controls) and improvement in HRCT findings of PIBO patients[29,31]; however, data in PIBO are limited to small case series[22]. The immunological milieu and airway remodeling in post-transplant BOS may differ significantly from PIBO in previously healthy children, making direct application of these findings questionable. Emerging therapies like IVIG (27, n = 11) or tiotropium (28, n = 30) have been tested only in small, single-center cohorts without controls. Such anecdotal evidence is useful for hypothesis generation but cannot support routine clinical use. Similarly, the role of non-pharmacological interventions, such as pulmonary rehabilitation, remains hypothetical in PIBO due to the lack of robust pediatric trials[29]. Oxygen supplementation, while helpful in improving saturation value, does not appear to significantly improve spirometric parameters, supporting its role as supportive care rather than a disease-modifying treatment[1,29]. Lung transplantation remains the ultimate intervention for children with end-stage PIBO, but it is associated with severe complications, including early graft dysfunction and high rates of postoperative extracorporeal membrane oxygenation[32]; these inherent risks and complexities restrict its widespread applicability.

Table 6 Therapeutic interventions in post-infectious bronchiolitis obliterans children: Comparative efficacy, limitations, and strength of evidence for each strategy.

Ref.	Efficacy	Limitations
Systemic corticosteroid pulses (IPMT) (Yoon et al[17], 2015)	Short-term FEV1 gains; better IPMT response with bronchial wall thickening on pre-treatment CT	Small, uncontrolled series; no symptom scores, no pulmonary function test, growth suppression; adverse effects
ICS (Zheng et al[25], 2022) (Zhang et al[26], 2018)	↑ in FEV1, FVC of continuous ICS group over 12 months; improved small-airway flows in toddlers	Retrospective; modest cohorts; adherence bias; durability beyond 1 year unknown
Azithromycin (macrolide) (Li et al[31], 2014)	Clinical stability in 86% when combined with steroids	Uncontrolled; symptom-based outcomes; risk of resistance
Tiotropium (LAMA) (Teixeira et al[28], 2013)	Good acute FEV1 increase	Small cohort; no placebo; unknown long-term impact
Intravenous immunoglobulin (IVIG) (Yilmaz et al[27], 2023)	Improved oxygenation; fewer infections in severe cases	Retrospective; no comparator; high cost; limited availability

Because no randomized, post-infectious bronchiolitis obliterans -specific trials exist, all current treatments for children remain empirical. The following hierarchy ranks interventions by pediatric evidence strength. IPMT: Intravenous pulse methylprednisolone therapy; ICS: Inhaled corticosteroids; CT: Computed tomography; FVC: Forced vital capacity; FEV₁: Forced expiratory volume in one second.

Another recurring limitation is the absence of standardized diagnostic criteria and objective outcome measures. Studies differ in how they define PIBO, measure lung function, and report response to therapy, making meta-analyses unreliable[15]. Only a few studies, like Jung et al[4] and Kim et al[5], used quantitative CT or structured follow-up to correlate imaging with functional prognosis; however, the second study had a cohort of only 23 children and both studies lacked external validation.

Moreover, the vast majority of studies fail to account for potential confounders such as co-existing conditions, adherence to therapy, or socioeconomic factors that could influence outcomes. Very few include blinded assessment of spirometry, leading to possible measurement bias. Finally, the heterogeneity in reporting adverse effects of prolonged corticosteroid or macrolide therapy means that risk-benefit analyses remain incomplete.

The overall picture that emerges is clear: The current evidence base is too fragmented and low-quality to inform robust, standardized treatment algorithms for PIBO. Clinicians must remain cautious in interpreting apparent benefits from interventions that lack adequately powered, controlled trials. The field urgently needs prospective multicenter studies with larger, well-characterized cohorts, uniform diagnostic definitions, longer follow-up and standardized spirometric endpoints.

Additionally, future trials should include stratified analyses to identify which subgroups — based on age, pathogen, severity, or inflammatory phenotype — benefit from specific regimens. It is crucial to move beyond descriptive series and develop hypothesis-driven research, including randomized controlled trials of immunomodulators, antifibrotics, or biologic agents targeting airway remodeling.

Until then, current practice should emphasize timely diagnosis, close lung function monitoring, and individualized therapy while balancing the limited efficacy and potential harms of repeated systemic corticosteroid use. Careful monitoring of pulmonary function over time is crucial to identify patients who may benefit from novel therapies or intensified supportive interventions. Collaborative registries and harmonized data collection will be essential to close these evidence gaps and prevent children with PIBO from experiencing avoidable functional decline due to inadequate or delayed intervention.

In summary, the management of PIBO must evolve from empirical, fragmented care to evidence-informed practice. This transition will only be possible if the pediatric pulmonology community invests in methodologically rigorous studies that can deliver answers relevant to everyday clinical decision-making. Importantly, the broader impact of PIBO on children’s daily activities and quality of life must not be overlooked. Many pediatric patients experience chronic symptoms such as cough, exertional dyspnea, and frequent respiratory infections, which can limit inclusion in physical and social activities. Moreover, caregivers experience a significant burden, as families often face prolonged hospital stays, complex treatments, and emotional stress related to the uncertain prognosis. Therefore, future research should also prioritize patient-reported outcomes and caregiver quality of life measures to better guide holistic management strategies.

Table 5 provides a structured summary of the key studies, highlighting the methodological limitations and the overall low level of evidence.

Overall evidence is based on small, single-center pediatric cohorts (n often < 50) with heterogeneous designs and short or variable follow-up, limiting external validity.

Quantitative CT (Jung et al[4], Kim et al[5]) and inhaled steroids (Zheng et al[25], Zhang et al[26]) offer the most consistent pediatric-specific data, yet remain retrospective and uncontrolled.

Imaging studies highlight potential predictive markers (air trapping, mosaic attenuation), but there is no standardized quantitative cut-off.

Pulmonary function data are frequently heterogeneous, with variable definitions of “improvement” and inconsistent use of bronchodilator testing.

Systemic steroid pulse efficacy is inferred from case series and expert consensus[1], but lacks prospective pediatric trials.

Interventions such as corticosteroids, azithromycin, and FAM show promise in limited case series, but robust randomized trials are lacking, increasing the risk of selection bias and publication bias.

Novel therapies (IVIG, tiotropium, azithromycin combination) are hypothesis-generating only, without randomized evaluation in children.

Non-pharmacological approaches, like pulmonary rehabilitation, remain under-investigated, with evidence often extrapolated from BOS post-transplant populations rather than PIBO specifically.

CONCLUSION

Managing PIBO in children can be challenging due to the lack of standardized treatments. Crucially, this field suffers from a deficit of multicenter, randomized controlled trials with sufficiently large cohorts to generate evidence capable of guiding clinical decision-making. Without such data, treatment remains fragmented and largely guided by individual clinician experience rather than scientific consensus. The complexity of PIBO demands a multidisciplinary, individualized treatment approach, but these are often not systematically implemented due to the lack of clear, evidence-based protocols. Moreover, it is imperative that future research focus on the identification of biomarkers, genetic factors, and individual risk profiles to develop targeted therapies. However, until these approaches transition from theory to clinical reality, meaningful improvements in long-term outcomes will remain elusive. Future research must address these gaps through prospective multicenter studies, standardized diagnostic criteria, and longer follow-up with robust pulmonary function endpoints, in order to establish evidence-based guidelines for pediatric PIBO management.