Expert opinion on emerging drugs for lung chronic graft-versus-host disease

Lung chronic graft-versus-host disease (cGVHD) is a rare, severe complication after allogeneic hematopoietic stem cell transplantation (HSCT), with high morbidity and mortality rates. Early recognition and treatment, which still represent an unmet need in the field, are the key to preventing permanent airways obstruction and lung fibrosis. National Institute of Health (NIH) recognized bronchiolitis obliterans (BO) and bronchiolitis obliterans syndrome (BOS) as the only accepted diagnostic or distinctive forms of lung cGVHD. The incidence may vary from 3% to 10% among HSCT recipients and 14% among patients with other signs of cGVHD [1]. Clinical manifestations of overt BOS include cough, dyspnea, and wheezing, although in its early phases many patients could be asymptomatic; indeed, screening with pulmonary function test (PFT) is highly recommended beginning on day +100 post-HSCT. A 6 minute walking test (6MWT) can play an important role in defining the functional status of patients and in measuring the response to therapeutic interventions in patients with BOS [2]. BO/BOS is characterized by irreversible narrowing and obliteration of the small airways [1], due to intraluminal connective tissue and chronic inflammation. Distal mucostasis, aggregates of macrophages and bronchiectasis may develop late. Studies on HSCT murine models showed the pathogenic role of thymic injury, macrophages recruitment, aberrant activation of Tand B-cells with local antibody production in airway damage [1,3]. Different pathways have been recognized leading to biologicaldriven therapeutic approaches. Although the definitive diagnosis of BO/BOS requires histologic demonstration of pulmonary fibroproliferative disorder, lung biopsy is seldom feasible in HSCT recipients. Thus, clinical diagnosis is largely based on PFT, as defined by the 2014 NIH criteria [4]: briefly, FEV1/vital capacity < . 7 or the fifth percentile of predicted, FEV1 < 75% of predicted with ≥10% decline over less than 2 years, not corrected with albuterol, and absence of documented infection in the respiratory tract. High-resolution chest computed tomography (HRCT) is useful in better defining airways obstruction and air trapping, but also in the differential diagnosis of pulmonary infections [4,5]. Likewise, bronchoscopy with bronchoalveolar lavage, nasal wash, and viral screening are also recommended to rule out infections [4–6]. In parallel with CT-documented air trapping, evidence of air trapping by PFT, defined by residual volume/total lung capacity (RV/TLC) elevated outside the 90% confidence interval or RV >120% of predicted, supports the diagnosis of BOS [4]. However, not all post-HSCT lung impairment disorders fulfill the NIH criteria for lung cGVHD. A PFT restrictive pattern (namely a consensual reduction of FEV1 and FVC, reflecting air trapping by small airway obstruction) is not currently recognized as a chronic GVHD manifestation, as it may be due to interstitial lung impairment but can also be caused by extra parenchymal processes [1,4,5]. Moreover, other forms of post-transplant lung impairment such as bronchiolitis obliterans organizing pneumonia, cryptogenic organizing pneumonia, interstitial pneumonia are considered as potentially associated with cGVHD but not diagnostic. Plethysmography is the preferred means to measure TLC to further define the emergence of a restrictive ventilatory defect. But, as in the lung transplantation setting, serial TLC monitoring is not routinely performed in HSCT recipients [7].