Summary for Clinicians: Clinical Practice Guideline for the Detection of Bronchiolitis Obliterans Syndrome after Pediatric Hematopoietic Stem Cell Transplant

Summary of: Shanthikumar S, Gower WA, Srinivasan S, Rayment JH, Robinson PD, Bracken J, et al. Detection of bronchiolitis obliterans syndrome after pediatric hematopoietic stem cell transplantation: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2024;210:262–280.

Hematopoietic stem cell transplant (HSCT) is an established treatment for many pediatric malignant and nonmalignant conditions with increasing rates each year worldwide. Although overall survival after HSCT has improved, pulmonary complications are the leading cause of nonrelapse mortality (1). Bronchiolitis obliterans syndrome (BOS), a manifestation of chronic graft-versus-host disease (cGvHD) in the lung, is characterized by progressive obstructive lung disease and is associated with high morbidity and mortality. The diagnosis of BOS is challenging because the initial phases are often asymptomatic; therefore, screening with pulmonary function testing (PFT) is recommended (2). Current international guidelines lack a clear standardized approach to post-HSCT monitoring. In addition, the current diagnostic criteria are largely extrapolated from adult data and are contingent on spirometry, which many children struggle to perform reliably.

The American Thoracic Society convened a multidisciplinary panel of international experts focusing on evaluation of BOS in children (3). A systematic review of the literature was performed. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations (Table 1). Ten recommendations were made on the role of screening PFT and diagnostic testing in children with suspected post-HSCT BOS (Table 2). Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed (Table 3).

Table 1.

Implications of strong and conditional recommendations

	Strong Recommendation (“We Recommend…”)	Conditional Recommendation (“We Suggest…”)
For patients	The overwhelming majority of individuals in this situation would want the recommended course of action, and only a small minority would not.	The majority of individuals in this situation would want the suggested course of action, but a sizable minority would not.
For clinicians	The overwhelming majority of individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.	Different choices will be appropriate for different patients, and each patient must be helped to arrive at a management decision consistent with her or his values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working toward a decision.
For policymakers	The recommendation can be adapted as policy in most situations, including for use as a performance indicator.	Policy making will require substantial debates and involvement of many stakeholders. Policies are also more likely to vary between regions. Performance indicators would have to focus on the fact that adequate deliberation about the management options has taken place.

Table 2.

Summary of recommendations for surveillance and diagnosis of BOS in pediatric HSCT

Diagnostic Study	Indication and Overview	Strength of Recommendation	Quality of Evidence
Pre-HSCT screening PFT	Pre-HSCT baseline spirometry, static lung volumes, and DlCO are recommended for all children who can perform PFT	Strong	Moderate certainty
Post-HSCT surveillance PFT	Active surveillance of spirometry and, when feasible, static lung volumes and DlCO are suggested in patients not at high risk of BOS, at intervals of •Every 3 mo in the first yr post-HSCT •Every 3–6 mo in the second yr post-HSCT More frequent testing may be indicated in high-risk individuals or those with cGvHD in other organs.	Conditional	Low certainty
	Long-term follow-up of spirometry and, when feasible, static lung volumes and DlCO are suggested in asymptomatic patients, at intervals of: •Every 6 mo in the third yr post-HSCT •Annually until 10 yr post-HSCT More frequent testing (3–6-monthly) may be necessary in patients with ongoing symptoms or until lung functions stabilize.	Conditional	Low certainty
MBW	At centers with adequate expertise, the panel suggests: •Pre-HSCT screening of MBW and spirometry or MBW alone if spirometry is not feasible	Conditional	Low certainty
	•Post-HSCT use of MBW and spirometry in individuals with suspected BOS or MBW alone if spirometry is not feasible	Conditional	Very low certainty
Chest CT	Pre-HSCT chest CT, with inspiratory and expiratory views, is suggested in all children before allogeneic HSCT Exceptions may apply to individuals with low risk of lung disease or those with radiation sensitive conditions (i.e., Fanconi anemia).	Conditional	Low certainty
	Post-HSCT chest CT, with inspiratory and expiratory views, is recommended for all children with suspected BOS Abnormal PFT should be repeated after 2 wk before performing chest CT to assess for an alternative cause such as infection or poor technique.	Conditional	Low certainty
Bronchoscopy with BAL	In post-HSCT patients with suspected BOS to rule out infection	Conditional	Very low certainty
Lung biopsy	In post-HSCT patients with suspected BOS and uncertainty regarding the diagnosis when: •Clinical evidence (clinical background/CT scan/PFT) is discordant •There is no alternative way to make the diagnosis •There is concern for an alternative/coexisting condition •The risk of biopsy is less than the risk of uncertainty	Conditional	Low certainty

Definition of abbreviations: BAL = bronchoalveolar lavage; BOS = bronchiolitis obliterans syndrome; cGvHD = chronic graft-versus-host disease; CT = computed tomography; Dl_CO = diffusing capacity of the lung for carbon monoxide; HSCT = hemopoietic stem cell transplant; MBW = multiple-breath washout; PFT = pulmonary function testing.

Table 3.

Proposed new criteria for diagnosis of post–HSCT BOS in children, based on modified Delphi process from a working group of the American Thoracic Society

Criteria
In children who can perform spirometry (GLI to be used for the reference equations for spirometry and plethysmography)
•Relative decline of FEV1 percent predicted compared with pre-HSCT baseline by 15% that persists on two tests at least 2 wk apart. AND Supporting features (two or more of the following): ○FEV1/FVC below lower limit of normal ○Evidence of air trapping on expiratory CT ○Evidence of air trapping on plethysmography (residual volume or residual volume/total lung capacity elevated above the upper limit of normal) ○Lung clearance index >8.0 ○cGvHD (active or past history) in another organ AND •Persistence of suspicion of BOS after directed treatment or expected resolution of any identified infection. Assessment of infection should include investigations directed by clinical symptoms, such as chest radiographs, CT scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral testing, sputum culture, bronchoalveolar lavage).
In children who cannot perform spirometry
•Clinical symptoms (i.e., wheeze, shortness of breath with activity) AND Two or more of the following ○Evidence of air trapping on expiratory CT ○Lung clearance index >8.0 ○cGvHD (active or past history) in another organ AND Persistence of suspicion of BOS after directed treatment or expected resolution of any identified infection. Assessment of infection should include investigations directed by clinical symptoms, such as chest radiographs, CT scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral testing, sputum culture, bronchoalveolar lavage).

Definition of abbreviations: BOS = bronchiolitis obliterans syndrome; cGvHD = chronic graft-versus-host disease; CT = computed tomography; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; GLI = Global Lung Function Initiative; HSCT = hemopoietic stem cell transplant.

This document is a summary of the clinical practice guideline for surveillance and detection of BOS in children after allogeneic HSCT (Figure 1). Clinicians should tailor these recommendations to individual patients’ clinical needs.

Figure 1.

Surveillance and diagnostic algorithm of bronchiolitis obliterans syndrome (BOS). Reprinted from Reference 3. *Some children may be unable to complete pulmonary function testing (PFT), in which case they can be omitted. Multiple-breath washout (MBW) can be assessed in addition to spirometry where available or as an alternative to spirometry if spirometry is not feasible. ^†A computed tomography (CT) scan, with inspiratory and expiratory views, is recommended in those with PFT results suggestive of BOS or if there are persistent clinical signs and symptoms of BOS with normal lung function. ^‡We suggest bronchoalveolar lavage to assess for infection in all cases of suspected BOS, even if the CT scan is normal. If the CT scan is normal, it is reasonable to repeat PFT 2 weeks after CT; those with complete resolution of symptoms/lung function impairment can return to normal surveillance. If the bronchoalveolar lavage reveals infection, this should be treated and clinical assessment should be repeated. Ongoing symptoms/signs or lung function impairment may signify BOS, and the pathway should be followed. ^§In cases in which there is uncertainty about the BOS diagnosis or suspicion of an alternative/coexisting condition based on the clinical presentation, a biopsy is suggested. Dl_CO = diffusing capacity of the lung for carbon monoxide; exp = expiratory; HSCT = hemopoietic stem cell transplant; insp = inspiratory.

Pre-HSCT Screening PFT

• • We recommend pre-HSCT spirometry, static lung volumes, and diffusing capacity of the lung for carbon monoxide (Dl_CO) for children who can perform them (strong recommendation, moderate certainty of evidence)

Strong evidence exists of high rates of pre-HSCT PFT abnormalities in children, many of whom are asymptomatic, prompting the need for screening PFT (4). Pre-HSCT PFT data provide a baseline for interpretation for post-transplant change. Identification of pre-HSCT abnormalities allows therapeutic interventions and identification of at-risk individuals who need close monitoring. The panel recognized that pre-HSCT PFT may be less useful in subsets of patients who cannot perform PFT reliably, including younger children, children with developmental delay, and those who are too unwell to perform the test. Efforts to develop alternative PFT techniques will expand pre-HSCT respiratory assessment to those who currently cannot perform PFT reliably.

Post-HSCT Surveillance PFT

• • We suggest active surveillance rather than testing only symptomatic patients using spirometry and, when feasible, static lung volumes, and Dl_CO beginning at 3 months post-HSCT (conditional recommendation, low certainty of evidence).
• • We suggest spirometry and, when feasible, static lung volumes and Dl_CO be performed every 3 months in the first year post-HSCT and every 3 to 6 months in the second year post-HSCT in patients not at high risk of BOS (conditional recommendation, low certainty of evidence).

• Comment: More frequent testing may be indicated in those at high risk of pulmonary complications or with cGvHD in other organs.

• • For long-term follow-up in asymptomatic patients, we suggest surveillance using spirometry and, when feasible, static lung volumes and Dl_CO every 6 months in the third year post-HSCT and yearly after 3 years, lasting until 10 years post-HSCT (conditional recommendation, low certainty of evidence).

• Comment: In patients with ongoing symptoms, more frequent (3–6 monthly) spirometry may be necessary until stability in lung function testing has been demonstrated.

The primary benefit of surveillance lung function tests is for early detection of pulmonary complications, including BOS. The panel concluded that the available literature supported the use of surveillance PFT, albeit with a low certainty of evidence. The frequency and intervals of testing are based on the panel’s consensus expert opinion, because there is a lack of evidence to support an optimal frequency. The literature in this field consists mainly of single-center retrospective studies, and the panel noted the need for multicenter prospective data that can assess the impact of different surveillance strategies based on risk stratification and outcomes.

Multiple-Breath Washout

• • At centers with adequate technical expertise to perform multiple-breath washout (MBW), we suggest including MBW and spirometry as part of a pre-HSCT assessment of pulmonary function or MBW alone if spirometry is not feasible (conditional recommendation, low certainty of evidence).
• • At centers with adequate technical expertise to perform MBW, we suggest the use of post-HSCT MBW as part of the diagnostic evaluation of suspected BOS, either as a complementary tool to spirometry or alone if spirometry is not feasible (conditional recommendation, very low certainty of evidence).

MBW is an effort independent test that allows lung function testing in those who cannot perform spirometry and in those as young as preschool age children. It may detect changes in peripheral airways that may be more sensitive for BOS detection. The lung clearance index is the outcome measure generated by MBW. A higher lung clearance index threshold improves the sensitivity and specificity of the test in detecting BOS (5, 6). The panel concluded that the certainty of evidence for the use of MBW is low because most studies were small, single-center studies with inconsistent testing methods and thresholds. MBW is recommended in sites with adequate technical expertise and in those where spirometry is not feasible; however, it should be regarded as an adjunct test. Limitations of MBW include the length of time needed to perform the test and the technical expertise required to administer the test. Future research should include studying the frequency of MBW measurements and its role in monitoring progression of BOS or response to therapy.

Chest Computed Tomography

• • We suggest performing a chest computed tomography (CT) scan, with inspiratory and expiratory views, in all children before allogeneic HSCT (conditional recommendation, low certainty of evidence).

• Comment: In situations in which the clinical team identifies a low risk of preexisting lung disease, it is reasonable not to perform a pre-HSCT CT scan. In addition, a pre-HSCT CT scan does not need to be performed in patients with an ionizing radiation sensitive condition (i.e., Fanconi anemia).

• • We suggest performing a chest CT scan with inspiratory and expiratory views in all children after allogeneic HSCT who develop obstructive lung function or in those children with clinical suspicion of BOS (conditional recommendation, low certainty of evidence).

Adult criteria highlight the role of chest CT scans for the diagnosis of BOS, but less consistent data are available for children. Chest CT is considered a noninvasive way to assess lung parenchyma and can provide respiratory assessment in those who cannot perform PFT. Evidence shows that chest CT findings of air trapping correlate well with BOS and that chest CT may also be used to assess for alternative pathologies (7). Inspiratory and expiratory imaging are needed to fully evaluate air trapping noted in BOS and may require additional technical expertise (3). The panel debated the need for pre-HSCT scans in all children; clinical discretion was recommended on an individual case basis. The panel concluded that chest CT should be performed in cases of suspected BOS in combination with PFT. Future research is needed to study optimal techniques of quantitative CT and chest magnetic resonance imaging.

Bronchoscopy with Bronchoalveolar Lavage

• • We suggest that bronchoscopy with bronchoalveolar lavage (BAL) be performed to assess for infection as part of the BOS evaluation (conditional recommendation, very low certainty of evidence).
• • Comment 1: If the PFT result is unreliable because of technique, it is reasonable to repeat the test in 1–2 weeks and then only perform the bronchoscopy if the suspicion of BOS persists.
• • Comment 2: When an infection has been diagnosed via a less invasive method (i.e., nasopharyngeal swab, sputum), it is reasonable to delay the bronchoscopy while treating the infection/waiting for the infection to resolve and then only perform the bronchoscopy if the clinical suspicion of BOS persists.

Diagnosis of BOS requires ruling out infection; BAL may be the best method to do so in patients with PFT decline suspected to have BOS. Although no studies have directly addressed this in a pediatric population, one study demonstrated that a significant proportion of patients suspected of BOS who underwent BAL actually had asymptomatic infection (8). Infection can also coexist with BOS. Future research is needed to investigate the role and outcomes of bronchoscopy with BAL in the evaluation of BOS.

Lung Biopsy

• • We suggest surgical lung biopsy in pediatric post-HSCT patients in whom BOS is suspected but uncertainty regarding the diagnosis exists and the risks of biopsy are smaller than the risks of the uncertainty (conditional recommendation, low certainty of evidence).
• •Comment: Uncertainty regarding the diagnosis exists when 1) clinical evidence (clinical background/CT scan/PFT) is discordant, 2) there is no alternate way to make the diagnosis, and 3) there is concern for an alternative or coexisting condition.

If clinical criteria for BOS are not met and alternative diagnoses are possible, lung biopsy may be the most timely and definitive method to guide management. Furthermore, although there are currently no data to support better outcomes with this approach, the histopathology from lung biopsy, in particular the presence of active inflammation versus fibrosis without inflammation, may guide therapy. A surgical or video-assisted thoracoscopic approach is preferred over transbronchial biopsy. Risks versus potential benefits must be weighed on an individual basis. The panel recommended a multicenter registry to study the utility of lung biopsy in this setting.

Proposed Criteria for Diagnosis of BOS after Pediatric HSCT

The 2014 National Institutes of Health cGvHD consensus diagnostic criteria are widely used for the diagnosis of post-HSCT BOS (9) on the basis of the use of spirometry and extrapolated from adult data. However, applicability to the pediatric population is currently unclear. There are several limitations to the current National Institutes of Health criteria, which include reliance on spirometry alone for diagnosis, use of outdated PFT reference equations, use of a fixed forced expiratory volume in 1 second threshold, and the requirement for the absence of infection (10). Furthermore, there have been several cases of biopsy-proven BOS that do not fulfill the current criteria for diagnosis (6). The panel used a modified Delphi process to develop new criteria for the diagnosis of post-HSCT BOS in children (Table 3). Two sets of criteria were developed: one for children who can perform spirometry and one for those who cannot (3).

Conclusions and Future Directions

This article summarizes the recommendations for detection of post-HSCT BOS in children on the basis of available evidence and expert opinion. Current evidence in the field of pediatric BOS after HSCT consists predominantly of retrospective, single-center studies, making evidence-based clinical practice guidelines challenging. Given its prevalence and significant morbidity and mortality, there is a need for multicenter prospective studies to assess novel surveillance techniques and biomarkers for early detection of BOS. Moreover, children undergoing HSCT represent heterogeneous clinical phenotypes, and patients would benefit from a personalized surveillance plan that optimizes the ability to detect BOS while minimizing burden and risk.