Lung GVHD: Key Insights Into Pulmonary Graft-Versus-Host Disease

Pulmonary graft-versus-host disease (GVHD) is a serious complication following allogeneic hematopoietic stem cell transplantation, often leading to severe respiratory impairment. It occurs when donor immune cells attack the recipient’s lung tissues, causing inflammation and fibrosis. This condition significantly affects quality of life and long-term survival, making early recognition and management critical.

Understanding the factors contributing to lung GVHD, its effects on pulmonary structures, and the best diagnostic and treatment approaches is essential.

Immune-Related Triggers

Pulmonary GVHD develops due to complex immune mechanisms driven by donor-derived immune cells. A key trigger is alloreactive T cells recognizing host lung antigens as foreign, initiating an inflammatory cascade. This is worsened by disrupted immune tolerance, where regulatory T cells (Tregs) fail to suppress excessive immune activation. A lower Treg-to-effector T cell ratio correlates with increased disease severity (New England Journal of Medicine, 2017).

Cytokine dysregulation further amplifies lung injury. Elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ) drive persistent inflammation and fibrosis. Patients with high post-transplant IL-6 levels have a significantly increased risk of developing pulmonary GVHD (Blood, 2020), suggesting cytokine profiling as a potential predictive biomarker.

B cells contribute to immune dysregulation by producing alloantibodies targeting host lung tissues. Donor-derived autoantibodies have been linked to increased epithelial injury and fibrosis (American Journal of Respiratory and Critical Care Medicine, 2021). Aberrant B cell activation also leads to tertiary lymphoid structures in the lungs, sustaining chronic inflammation and tissue remodeling.

Infections can exacerbate pulmonary GVHD by further stimulating immune responses. Reactivations of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have been associated with heightened immune activity, accelerating lung damage. A retrospective study found CMV reactivation doubled the incidence of pulmonary GVHD (The Lancet Haematology, 2019), highlighting infections as key modulators of immune response.

Pulmonary Structures Impacted

Pulmonary GVHD primarily affects the small airways, particularly the bronchioles, often leading to obliterative bronchiolitis (OB). This condition arises as bronchiolar epithelium undergoes fibrosis, causing luminal narrowing and air trapping. Histopathological studies show epithelial denudation, subepithelial fibrosis, and mononuclear cell infiltration, contributing to airflow obstruction (American Journal of Respiratory and Critical Care Medicine, 2021). Pulmonary function tests typically reveal a decline in forced expiratory volume in one second (FEV1) without significant changes in total lung capacity, distinguishing it from restrictive pulmonary disorders.

Beyond the bronchioles, alveolar structures also undergo alterations, particularly in cases with diffuse interstitial involvement. Persistent alveolar injury impairs gas exchange and reduces lung compliance. Lung biopsies frequently show alveolar wall thickening due to collagen deposition (The Lancet Respiratory Medicine, 2020). Microvascular damage further exacerbates hypoxemia, as capillary endothelial cells become more permeable and eventually obliterate. High-resolution computed tomography (HRCT) scans often reveal reticular opacities and traction bronchiectasis, indicating fibrotic distortion of lung parenchyma.

Though less common, pleural involvement can also contribute to respiratory dysfunction. Pleural thickening or effusions may restrict lung expansion and worsen dyspnea. Thoracentesis with fluid analysis helps differentiate GVHD-related effusions from infectious or malignant causes. Findings typically include an exudative profile with elevated lactate dehydrogenase (LDH) levels, consistent with inflammatory processes (Chest, 2019).

Clinical Features

Patients with pulmonary GVHD often experience progressive respiratory symptoms over weeks to months. Exertional dyspnea is one of the earliest and most common complaints, gradually worsening as airflow obstruction and fibrosis advance. Unlike infectious complications, pulmonary GVHD has an insidious onset, which can delay diagnosis.

A persistent dry cough frequently accompanies dyspnea, often signaling small airway involvement. This cough is typically non-productive, distinguishing it from the mucus-laden expectoration seen in infections. Wheezing may also develop due to bronchiolar narrowing, though it is often resistant to standard bronchodilator therapy due to underlying fibrosis. Pulmonary function tests typically reveal an obstructive pattern with a reduced FEV1/FVC ratio, and in some cases, a mixed obstructive-restrictive pattern when interstitial fibrosis is also present. A decline in FEV1 of more than 10% over six months is predictive of poorer outcomes.

Hypoxemia becomes more prominent in later stages, particularly during exertion, as alveolar damage and microvascular remodeling impair gas exchange. Some patients develop oxygen desaturation during routine activities, requiring supplemental oxygen therapy. Chronic hypoxia can lead to pulmonary hypertension, worsening respiratory distress. Clubbing of the fingers has been observed in individuals with prolonged disease, reflecting chronic hypoxemia and vascular remodeling. Fatigue and unintended weight loss often accompany pulmonary GVHD due to increased respiratory effort and systemic inflammation.

Distinctions in Imaging and Pathology

Radiologic and histopathologic findings help distinguish pulmonary GVHD from other post-transplant complications. HRCT plays a central role, with obliterative bronchiolitis (OB) presenting as mosaic attenuation due to air trapping on expiratory imaging. This pattern results from heterogeneous small airway obstruction, often with bronchial wall thickening and centrilobular nodules. When pulmonary GVHD involves interstitial fibrosis, HRCT reveals reticular opacities and traction bronchiectasis, indicating progressive parenchymal remodeling. These findings contrast with infectious pneumonias, which typically show consolidations or ground-glass opacities without mosaic perfusion.

Histopathologic examination provides deeper insights into disease progression. In OB-dominated cases, bronchiolar epithelium exhibits subepithelial fibrosis with dense mononuclear infiltration, leading to luminal narrowing. Advanced disease stages show complete obliteration of bronchiolar lumens, distinguishing GVHD from other post-transplant obstructive lung diseases. When alveolar involvement is present, histologic sections demonstrate collagen deposition within the interstitium, resembling patterns seen in idiopathic pulmonary fibrosis but with a more patchy distribution.

Diagnostic Methods

Diagnosing pulmonary GVHD requires clinical assessment, pulmonary function testing, imaging, and histopathologic analysis to differentiate it from other post-transplant complications. Since early symptoms can be nonspecific, a structured approach is necessary to detect the disease before irreversible lung damage occurs.

Pulmonary function tests (PFTs) are essential, with a decline in FEV1 of more than 10% over six months being a strong indicator of progressive small airway disease. A reduced FEV1/FVC ratio with preserved or mildly reduced total lung capacity suggests an obstructive pattern typical of obliterative bronchiolitis. When interstitial involvement is suspected, diffusion capacity for carbon monoxide (DLCO) is often diminished, reflecting impaired gas exchange. Serial PFTs help monitor disease progression, as functional changes can precede radiographic abnormalities.

Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy can help rule out infections and other inflammatory lung conditions. BAL fluid analysis may show elevated neutrophil counts, though this finding is not exclusive to pulmonary GVHD. In cases requiring a definitive diagnosis, surgical lung biopsy provides the highest diagnostic yield, particularly for distinguishing obliterative bronchiolitis from other post-transplant lung pathologies. Given the risks of invasive procedures, biopsy is reserved for cases where imaging and functional testing are inconclusive.

Factors Influencing Disease Course

Several factors influence pulmonary GVHD progression and response to therapy. These include patient characteristics, transplant-related variables, and post-transplant complications.

The degree of HLA mismatch between donor and recipient significantly affects disease risk. Greater genetic disparity increases the likelihood of immune-mediated lung injury. Patients receiving grafts from unrelated or haploidentical donors exhibit a higher incidence of pulmonary GVHD compared to those with fully matched sibling donors. Peripheral blood stem cell grafts, which contain more alloreactive T cells, are associated with a greater risk of chronic GVHD, including lung involvement.

Post-transplant complications such as infections and systemic GVHD also impact pulmonary outcomes. CMV reactivation has been linked to accelerated lung fibrosis, while systemic GVHD affecting the skin, liver, or gastrointestinal tract often correlates with more aggressive pulmonary manifestations. Multisystem involvement suggests heightened inflammation, contributing to rapid pulmonary decline. Long-term immunosuppressive therapy, while necessary to control GVHD, increases susceptibility to opportunistic infections and drug-related pulmonary toxicity, complicating disease management.