Pulmonary Graft-Versus-Host Disease After Hematopoietic Cell Transplantation

Abstract

Pulmonary complications, particularly bronchiolitis obliterans syndrome (BOS), affect outcomes after hematopoietic cell transplantation. This article provides practical guidelines for diagnosing and managing BOS and other noninfectious pulmonary complications, based on experience at a large transplant center and current literature. Early BOS recognition through pulmonary function tests and high-resolution computed tomography is necessary, followed by a stepwise treatment approach involving corticosteroids; fluticasone, azithromycin, and montelukast therapy; and second-line agents. The article also details the differential diagnosis of BOS, including cryptogenic organizing pneumonia and interstitial pneumonia, offering a framework and case study for managing these complex complications.

AT A GLANCE

• ■ BOS affects as many as 20% of patients with chronic graft-versus-host disease and is the most frequent late-phase pulmonary complication post–hematopoietic cell transplantation.

• ■ Early recognition of BOS through screening is crucial because patients are often asymptomatic in its initial stages.

• ■ BOS treatment depends largely on the presence of other chronic graft-versus-host disease organ involvement.

Pulmonary complications cause morbidity and mortality after hematopoietic cell transplantation (HCT). These complications vary depending on the time post-HCT and can be broadly classified as infectious or noninfectious. Improvements in outcomes for infectious pulmonary complications underscore the importance of addressing noninfectious complications. The most common noninfectious pulmonary complications include periengraftment respiratory distress syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, drug toxicity, cryptogenic organizing pneumonia (COP), and bronchiolitis obliterans syndrome (BOS) (Harris et al., 2024; Seval et al., 2018).

During the late-phase post-HCT period (after day 100), noninfectious pulmonary complications include BOS, interstitial lung disease, pulmonary hypertension, and drug toxicity. BOS is the most common cause of late-phase pulmonary complications post-HCT, affecting as many as 20% of patients with chronic graft-versus-host disease (GVHD) (Bos et al., 2024). Currently, there is no standardized approach to managing pulmonary chronic GVHD. This article aims to provide practical guidelines and share clinical management policies from John Theurer Cancer Center, a transplant center at Hackensack University Medical Center in New Jersey performing more than 400 HCTs annually.

BOS

BOS is the only recognized manifestation of pulmonary GVHD. However, diagnosis is often challenging because of overlap with other pulmonary complications, limitations in confirmatory testing, and risks associated with invasive procedures that clinicians use to identify the underlying etiology. BOS affects as many as 5.5% of HCT recipients and as many as 20% of those with chronic GVHD (Bos et al., 2024; Seval et al., 2018).

Early recognition of BOS through screening is necessary because patients are often asymptomatic in its initial stages. Although BOS rarely presents as an isolated manifestation of chronic GVHD, BOS typically coexists with other organ involvement. The median time to BOS diagnosis is 1.5 years post-HCT and six months following a chronic GVHD diagnosis; patients often present with dry cough and dyspnea in the absence of infection (Fraebel et al., 2023; Harris et al., 2024). Serial pulmonary function tests (PFTs) and high-resolution chest computed tomography (CT) scans can evaluate declines in pulmonary function and/or the presence of air trapping.

A BOS diagnosis requires the exclusion of other causes of airflow obstruction, such as infection, asthma, and chronic obstructive pulmonary disease. The National Institutes of Health Chronic GVHD Consensus Conference established diagnostic criteria for BOS to standardize its definition (Chien et al., 2010; Fraebel et al., 2023). These criteria include the following (Jagasia et al., 2015):

• ■ Decreased forced expiratory volume in one second (FEV1) (less than 75% predicted with a decline of more than 10% in less than two years or from pre-HCT baseline)

• ■ Absence of infection in the respiratory tract

• ■ Evidence of airway obstruction with FEV1/forced vital capacity (FVC) ratio less than 0.7 and air trapping

• ■ Elevated residual volume (greater than 120% predicted or residual volume/total lung capacity above the 90th percentile)

• ■ Air trapping on expiratory high-resolution CT (mosaic pattern) or lung biopsy

In the presence of extrapulmonary chronic GVHD, only the first four criteria are required for diagnosis. Other CT features of bronchiolitis may include centrilobular nodules, airway thickening, or bronchiectasis (Dickey et al., 2024; Fraebel et al., 2023).

Although BOS remains the most well-characterized and common pulmonary manifestation of chronic GVHD, researchers and clinicians are increasingly recognizing other phenotypes, and these may represent atypical presentations. These include mixed obstructive and restrictive patterns on spirometry (Archer et al., 2023; Pang et al., 2022). In such cases, the restrictive component often results from truncal sclerosis (scleroderma or visceral pleural fibrosis), a severe chronic GVHD manifestation. Clear definitions for mixed or restrictive pulmonary chronic GVHD are lacking, hindering their recognition in clinical practice.

BOS treatment (see Table 1) depends largely on the presence of other chronic GVHD organ involvement. Systemic corticosteroid therapy for chronic GVHD, often driven by other organ manifestations, typically involves prednisone (or equivalent) at 1 mg/kg per day with a slow taper over several months. In the absence of other organ involvement or if systemic corticosteroids are not required for other manifestations, treatment may consist of a pulse dose of steroids (1 mg/kg per day) for one to two weeks, followed by a four- to six-week taper. Because of the inherent infection risk, long-term corticosteroid use is not recommended for BOS without extrapulmonary chronic GVHD manifestations (Bos et al., 2024; Harris et al., 2024).

TABLE 1.

TREATMENT OF BRONCHIOLITIS OBLITERANS SYNDROME

TREATMENT TYPE	TREATMENT
Initial treatment	FAM and LABA ■ Fluticasone 440 mcg twice daily or combined inhaled corticosteroid with LABA ■ Azithromycin 250 mg 3 times weekly ■ Montelukast 10 mg once daily Prednisone ■ If asymptomatic with mild decline in FEV1 (greater than 70% predicted), there is no indication to increase or start prednisone. ■ If symptomatic or with a moderate to severe decline in FEV1 (less than 70% predicted), start or increase prednisone to 1 mg/kg per day (or equivalent) × 2 weeks, then taper over 4 weeks to a dose of 0.25 mg/kg per day or pre–bronchiolitis obliterans syndrome therapy dose by week 5.
Persistent FEV1 decline despite initial treatment	Consider other therapies such as photopheresis, ruxolitinib, belumosudil, and imatinib. As soon as FEV1 is stabilized, taper prednisone, as delineated above.
Tapering	After a minimum of 6 months of FAM and LABA, taper medications if pulmonary function tests with lung volumes remain stable (or improved) and if there are no new extrapulmonary chronic graft-versus-host disease manifestations. ■ Stop azithromycin first. Ensure spirometry and lung volumes remain stable after 3 months. ■ Next, stop montelukast. Ensure spirometry and lung volumes remain stable after 3 months. ■ Then, stop LABA and decrease the inhaled corticosteroid dose by 50% after 1 month. If stable after 1 month, taper off inhaled corticosteroids over 1–3 months. ■ Pulmonary rehabilitation ■ Oxygen supplementation to maintain oxygen saturation greater than 88% on room air
Supportive treatment	■ Pneumococcal, influenza vaccination ■ Encapsulated bacteria and Pneumocystis jiroveci pneumonia prophylaxis ■ Antifungal, antiviral prophylaxis ■ Pulmonary rehabilitation ■ Oxygen supplementation to maintain oxygen saturation greater than 88% on room air

FAM—fluticasone, azithromycin, and montelukast; FEV1—forced expiratory volume in 1 second; LABA—long-acting beta-2 agonist

Note. Based on information from Fred Hutchinson Cancer Center, 2024.

Adjunctive therapy with fluticasone, azithromycin, and montelukast has demonstrated efficacy in slowing pulmonary function decline and reducing steroid requirements (Fraebel et al., 2023; Williams, 2017). Given the generally irreversible nature of lung function impairment in BOS, the treatment goals are to prevent further decline and to stabilize lung function. Second-line options for refractory cases include belumosudil, imatinib, ruxolitinib, and extracorporeal photopheresis (Dickey et al., 2024; Jagasia et al., 2021). Although ibrutinib is approved by the U.S. Food and Drug Administration for chronic GVHD, it is generally considered less favorable for pulmonary chronic GVHD because of the associated risks of infection and bleeding (Bos et al., 2024).

Supportive care measures focus on prevention and include annual influenza vaccination, four doses of pneumococcal conjugate vaccine post-HCT, antimicrobial prophylaxis against encapsulated organisms and Pneumocystis jiroveci pneumonia, appropriate antiviral and antifungal prophylaxis for patients receiving systemic immunosuppression, and consideration of immunoglobulin replacement in patients with hypogammaglobulinemia (immunoglobulin G less than 400 mg/dl) and recurrent sinopulmonary infections (Bos et al., 2024).

The John Theurer Cancer Center employs a stepwise approach for managing patients diagnosed with BOS based on the National Institutes of Health’s consensus criteria. This approach focuses on PFT monitoring while assessing significant airflow obstruction for proactive intervention (see Figure 1).

FIGURE 1.

STEPWISE TREATMENT APPROACH FOR MANAGING PATIENTS DIAGNOSED WITH BOS

BOS—bronchiolitis obliterans syndrome; DLCO—diffusing lung capacity of carbon monoxide; FAM—fluticasone, azithromycin, and montelukast; FEV1—forced expiratory volume in 1 second; HCT—hematopoietic cell transplantation; ICS—inhaled corticosteroids; LABA—long-acting beta-2 agonist; PFTs—pulmonary function tests

PFTs (spirometry, lung volumes, and diffusing lung capacity of carbon monoxide) are recommended for asymptomatic allogeneic HCT recipients at 6 and 12 months post-transplantation (or at chronic GVHD onset). For patients with chronic GVHD, more frequent monitoring (every three to six months) assesses changes from baseline. Baseline PFTs are important for accurate comparison, given the reliance on PFTs for BOS diagnosis. The National Institutes of Health’s consensus criteria recommend repeat testing every three to six months for patients with BOS or those exhibiting a greater than 10% decline from baseline (Jagasia et al., 2015; Yang et al., 2022).

Clinicians assess for upper respiratory infections or other causes of significant airflow obstruction or decline. If BOS criteria are met, patients can initiate inhaled glucocorticoids with or without a long-acting beta-2 agonist. Clinicians can continue PFT monitoring every three months until FEV1 stabilizes for one year, then every six months for one year, and subsequently every 6–12 months. Patients continue treatment until FEV1 falls below 70% predicted or chronic GVHD resolves without exacerbation for at least six months after discontinuing immunosuppression.

Differential Diagnosis

It is essential to distinguish BOS from other noninfectious lung disorders, such as organizing pneumonia and interstitial pneumonia (see Table 2). COP, which used to be known as bronchiolitis obliterans organizing pneumonia, presents similarly to BOS and shares similar prognostic and treatment considerations (Harris et al., 2024). COP often manifests with dyspnea, fever, and nonproductive cough. Radiographic findings include diffuse or multifocal infiltrates, ground-glass opacities, and consolidation (Harris et al., 2024). In contrast, BOS is rarely associated with fever or infiltrates (Chien et al., 2010). PFTs in COP typically reveal a restrictive pattern with reduced FVC and diffusing lung capacity of carbon monoxide. Patients may present with symptoms of pneumonia but their infectious workup is negative or they do not respond to antibiotics. COP treatment involves corticosteroids (0.3–1 mg/kg per day), with anticipated improvement within one to two weeks. Steroid treatment duration ranges from 2 to 12 months (Fraebel et al., 2023).

TABLE 2.

BOS VERSUS COP (BOOP)

VARIABLE	BOS	COP (BOOP)
Symptoms	Nonproductive cough, dyspnea	Nonproductive cough, dyspnea, fever
Pulmonary function tests	Obstructive; decreased FEV1/FVC; normal TLC, DLCO; increased residual volume, residual volume/TLC	Restrictive, normal FEV1/FVC, decreased TLC and DLCO
Computed tomography	Air trapping (expiratory view), bronchiectasis, bronchial thickening	Consolidation, ground-glass opacities
Other	Only type of chronic pulmonary graft-versus-host disease	More often after viral syndrome
Treatment	1 mg/kg prednisone or pulse steroids over 1 month; fluticasone, azithromycin, and montelukast	1 mg/kg prednisone; total treatment is prolonged (2–12 months).

BOOP—bronchiolitis obliterans organizing pneumonia; BOS—bronchiolitis obliterans syndrome; COP—cryptogenic organizing pneumonia; DLCO—diffusing lung capacity of carbon monoxide; FEV1—forced expiratory volume in 1 second; FVC—forced vital capacity; TLC—total lung capacity

Note. Based on information from Chien et al., 2010; Fraebel et al., 2023.

Interstitial pneumonia, like COP, can present diagnostic challenges. Distinguishing between the two often requires a lung biopsy. Idiopathic pneumonia syndrome is characterized by respiratory symptoms, hypoxia, and pulmonary infiltrates after HCT without evidence of infection, fluid overload, or cardiac dysfunction. The median time to onset is two to three weeks post-HCT (Shiari et al., 2021). Radiographic findings in interstitial pneumonia typically include ground-glass opacities and consolidation (Shiari et al., 2021). PFTs generally reveal restrictive defects, although clinicians may also observe an obstructive pattern (Harris et al., 2024; Shiari et al., 2021). Treatment typically involves corticosteroids.

Case Presentation

A 55-year-old female presented to the institution for possible allogeneic HCT to treat relapsed acute myelogenous leukemia. Her pre-HCT evaluation showed no renal, hepatic, or cardiac abnormalities. Pre-HCT PFTs revealed a mildly reduced FVC (75%), an FEV1 of 79% (1.97 L), and a normal FEV1/FVC ratio (86%).

She subsequently received unrelated donor peripheral blood stem cells after a conditioning regimen with cyclophosphamide 60 mg/m² on days −3 and −2 and total body irradiation 150 cGy in divided fractions on days −7 to −4. Her hospital course was unremarkable, and she was discharged home 14 days after HCT.

She developed chronic GVHD of the skin at 11 months post-HCT and was treated with prednisone 1 mg/kg per day. Ruxolitinib was added two months later at the onset of scleroderma.

At 18 months after HCT, she presented with a nonproductive cough and increased dyspnea. Her pulse oximetry was 92% on room air. A respiratory viral panel was negative, and a chest CT revealed bronchiectasis and bronchial thickening without consolidation. There was mild hyperinflation of both lungs on expiratory view. She developed increasing fatigue and progressive weight loss, and a physical examination revealed decreased breath sounds bilaterally with an expiratory wheeze. PFTs revealed an airflow obstruction respiratory impairment with air trapping and an FEV1/FVC ratio of 58% and an FEV1 of 44% (1.4 L) that did not improve with bronchodilators. Residual volume was greater than 128%. An echocardiogram revealed a normal systolic ejection fraction without diastolic dysfunction.

Fluticasone, azithromycin, and montelukast plus a long-acting beta-2 agonist was initiated, and prednisone was pulse-dosed at 1 mg/kg per day for two weeks, then tapered over the subsequent four weeks down to the pre-BOS dose (20 mg per day). Photopheresis was added for concomitant effects. Three months later, there was stabilization of FEV1 percentage predicted. She did not experience new extrapulmonary manifestations of chronic GVHD and was tapered successfully off corticosteroids at 27 months post-HCT.

Conclusion

In conclusion, BOS remains a challenge post-HCT, affecting as many as 20% of patients with chronic GVHD. Early diagnosis through PFTs and high-resolution CT monitoring supports patient outcomes, given the often asymptomatic initial presentation. Although clinicians frequently employ systemic corticosteroids and fluticasone, azithromycin, and montelukast therapy, managing BOS requires a multifaceted approach including second-line agents for refractory cases and supportive care to minimize infectious complications. Accurate differentiation from other noninfectious pulmonary complications, such as COP and interstitial pneumonia, enhances management and relies on integrating clinical, radiographic, and pulmonary function data. The stepwise approach, emphasizing early detection and proactive intervention, provides a framework for optimizing outcomes in patients with BOS.

PROFESSIONAL DEVELOPMENT ACTIVITY.

EARN 1 CONTACT HOUR

ONS members can earn free nursing continuing professional development (NCPD) for reading this article and completing an evaluation online. To do so, visit www.ons.org/publications-research/cjon/ncpd to link to this article and then access its evaluation link after logging in. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation.

Certified nurses can claim no more than 1 total ILNA point for this program. Up to 1 ILNA point may be applied to Early Post-Transplant Management and Education OR Late Post-Transplant Management and Education OR Symptom Management, Palliative Care, Supportive Care. See www.oncc.org for complete details on certification.

Consider how you can apply findings from this article to your own practice using the following questions:

• ■ How does your current practice approach the early recognition and diagnosis of bronchiolitis obliterans syndrome in patients post–hematopoietic cell transplantation, and what improvements could be made to enhance early detection and intervention?

• ■ Can you identify any similar challenges your patients or coworkers have experienced with managing pulmonary graft-versus-host disease, and what approaches have been effective or could be improved based on the case study and guidelines presented in the article?

DO YOU HAVE AN INTERESTING TOPIC TO SHARE?

Advanced Practice discusses situations unique to advanced practice nurses. If you are interested in writing for this department, contact Associate Editor Mary Elizabeth Davis, DNP, RN, CHPN^®, AOCNS^®, at davism@mskcc.org.