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

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.

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.

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.

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.

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.

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.