Pulmonary Manifestations of Hematological Malignancies: Focus on Pulmonary Chronic Graft-Versus Host Disease
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Advances in the management of patients in terms of the diagnosis and treatment of hematologic malignancies and treatment-related complications, especially infectious complications, have increased survival time. However, more than half of the patients treated for hematologic malignancies will develop a pulmonary complication during their follow-up, infectious pneumonia remaining the most common diagnosis that should be considered first in regard to its potential severity. Otherwise, new complications that may involve different organs, including the lungs, have been increasingly reported. Currently, over a quarter of lung infiltrates occurring in the context of hematological diseases are due to noninfectious causes. Thus, lung physicians may be increasingly confronted with these lung disorders. Various noninfectious pulmonary complications have been described in the different hematological malignancies; however, these complications are most often studied in the context of allogeneic hematopoietic stem cell transplantation (HSCT). In this chapter, we will briefly review the lung diseases associated with various hematological malignancies before focusing on noninfectious pulmonary complications following allogeneic HSCT.
KeywordsAllogeneic stem cell transplantation Bronchiolitis obliterans Hematological diseases Lung complications Idiopathic pneumonia syndrome Infiltrative lung diseases
Advances in the management of patients in terms of the diagnosis and treatment of hematologic malignancies and treatment-related complications, especially infectious complications, have increased survival time. However, more than half of the patients treated for hematologic malignancies will develop a pulmonary complication during their follow-up, infectious pneumonia remaining the most common diagnosis that should be considered first in regard to its potential severity. Otherwise, new complications that may involve different organs, including the lungs, have been increasingly reported. Currently, over a quarter of lung infiltrates occurring in the context of hematological diseases are due to noninfectious causes . Thus, lung physicians may be increasingly confronted with these lung disorders. Various noninfectious pulmonary complications have been described in the different hematological malignancies; however, these complications are most often studied in the context of allogeneic hematopoietic stem cell transplantation (HSCT). In this chapter, we will briefly review the lung diseases associated with various hematological malignancies before focusing on noninfectious pulmonary complications following allogeneic HSCT.
Pulmonary Manifestations of Hematological Malignancies
Main drugs used for the management of patients with hematological malignancies known to induce lung toxicities 
Antibiotic chemotherapeutic agents
Bleomycin, Mitomycin C
Busulfan, Cyclophosphamide, Chlorambucil, Melphalan, Ifosfamide, Procarbazine
Methotrexate, 6-mercaptopurine, Cytosine arabinoside, Fludarabine
Bischloroethyl nitrosourea (BCNU), Chloroethyl cyclohexyl nitrosourea (CCNU), Methyl-CCNU
Other chemotherapeutic agents
All-trans retinoic-acid (ATRA), Imatinib mesylate, Dasatinib, Bortezomib
Interferons, anti-Interleukin-2, TNF alpha inhibitors, Sirolimus, Temsirolimus
Rituximab, Gemtuzumab ozogamicin, Alemtuzumab
Blood transfusion, GM-CSF, G-CSF
Nonspecific noninfectious pulmonary complications reported in hematological malignancies
Organizing pneumonia 
Sweet’s syndrome 
Alveolar proteinosis 
Lymphoma/chronic lymphocytic leukemia
Langerhans histiocytosis 
Venous thromboembolism 
Intra-alveolar hemorrhage 
Pulmonary edema 
Lung cancer 
Extramedullary hematopoiesis 
Sweet’s syndrome 
Diffuse infiltrative lung disease in the context of autoimmune disorders 
Eosinophilic pneumonia 
Alveolar proteinosis 
Organizing pneumonia 
Pulmonary hypertension 
Pulmonary Manifestations of Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic HSCT is used as a curative treatment in various tumoral and non-tumoral diseases. The patient's abnormal hematopoietic tissue is replaced with healthy stem cells.
The transplanted stem cells can be derived from bone marrow, peripheral blood or umbilical cord blood harvested from a related donor or a compatible unrelated donor. Before the transplantation procedure is performed, the host is prepared with a special conditioning regimen that usually involves fractionated total body irradiation and cytotoxic chemotherapy to prevent graft rejection and to eradicate any residual tumor cells. Until recently, the conditioning regimen was “myeloablative,” leaving the patient severely neutropenic for several weeks. Over the past few years, nonmyeloablative transplants have been developed based on the graft-versus leukemia/lymphoma principle, thereby eradicating residual tumor cells. The conditioning regimen for these transplants is attenuated, depressing only the host immune response and thus limiting the neutropenic period to just a few days. This means that allogeneic HSCT can now be extended to older and frailer patients with comorbidities who have had long-term treatment in the past, which has increased the number of allogeneic HSCT procedures performed. The major complications that occur after allogeneic HSCT are infections or the consequences of the immune reactions of GVHD, which can be either acute or chronic depending on the clinical features . For unknown reasons, unlike the skin, gastrointestinal tract and liver, the lungs have not been identified as a target of acute GVHD in humans. In contrast, lung involvement is common in chronic GVHD that may be either restricted to a single organ or tissue or widespread. Chronic GVHD is characterized by tissue destruction resulting in fibrosis and is associated with a process in which donor T cells recognize peptides presented by the major histocompatibility complex on antigen-presenting cells of the host. GVHD targets epithelial cells of various organs with an incidence that depends on various factors and most commonly occurs during unrelated transplantations and peripheral stem cell transplantations. Treatment of GVHD requires the maintenance or enhancement of immunosuppressive therapy. The prognosis of GVHD is primarily related to the severity of the initial response to corticosteroids. The occurrence of chronic GVHD affects the morbidity, mortality and the quality of life of patients .
Chronic Pulmonary Graft Versus Host Disease
Chronic lung GVHD has been identified, the diagnosis of which is based on histopathological observations performed during lung biopsies showing bronchiolitis obliterans (BO). Although BO is the only condition attributed to pulmonary GVHD , other clinico-histological lung conditions are known to be associated with GVHD, such as organizing pneumonia (OP, formerly named bronchiolitis obliterans organizing pneumonia, BOOP) [5, 7]. Other noninfectious diffuse infiltrative lung diseases have been described and may also be associated with GVHD . Although less frequent than BO, these diseases are often ignored, and their incidences may be underestimated.
Bronchiolitis obliterans (BO) is the main non-infectious late pulmonary complication in allogeneic HSCT recipients. This serious and potentially fatal complication typically develops in the first 2 years following transplant but also can occur several years later [9, 10]. The incidence of BO is difficult to assess; according to several retrospective studies, it varies from 2 to 26 % [11, 12, 13, 14, 15, 16]. This disparity is mainly due to the lack of consensus regarding the diagnostic criteria. The most recent study, which was based on the largest number of patients, reported a prevalence of 5.5 % . The incidence increased to 14 % in the subpopulation of patients who developed extrathoracic chronic GVHD . Over a period of 3 years, we conducted a prospective cohort study that included a systematic follow-up of lung function for all of the consecutive patients who underwent an allogeneic HSCT in our center. Out of the 243 enrolled patients scheduled to be engrafted, 202 were included at Day 100, with an 18-month cumulative incidence of BO estimated at 12.9 % (Study NCT01219972 ALLOPULM clinical trials, analysis in progress; ).
Numerous risk factors for BO have been proposed in various retrospective studies, including age of the donor or recipient, type of transplant, degree of HLA incompatibility, presence of gastroesophageal reflux, gammaglobulin levels, type of GVHD prophylaxis, type of conditioning regimen, underlying blood disorder, tobacco use or acute GVHD, with conflicting results . The only association reported in all of the studies was the occurrence of extrathoracic chronic GVHD at the time of BO diagnosis. One objective of our ALLOPULM study was to prospectively identify the events occurring within 3 months after transplantation that are associated with the subsequent occurrence of BO. Using multivariate analysis, we showed that a history of smoking, the occurrence of pulmonary infection, and pre-existing abnormal pre-transplant pulmonary function were associated with BO development .
Physiopathology of Bronchiolitis Obliterans
The exact pathogenesis of BO is still unknown. Epidemiological studies have shown an association between the development of BO and the presence of active chronic GVHD, which led to the hypothesis that BO is, in fact, chronic GVHD of the lung . The most important mechanism contributing to BO would then result from the immune-mediated attack of airway epithelial cells by donor T cells. As opposed to acute GVHD, chronic GVHD also involves B-cell stimulation, autoantibody synthesis and systemic fibrosis . Mouse models of chronic GVHD involve three disease mechanisms: autoantibody synthesis, pro-fibrotic processes and defective thymic function. Thymic damage leads to a decrease in TReg cell number and function and defective negative selection of T cells .
The recent development of an animal model of BO caused by allogeneic HSCT has revealed new pathophysiological pathways : the peribronchiolar inflammatory infiltrate is mainly composed of CD4 lymphocytes, Clara cells that regenerate bronchiolar epithelium may be targets and a large number of cytokines are produced during the process . More recently, the peribronchiolar deposition of alloantibodies was demonstrated in the same animal model, as was the role of mature B cells from the donor in the development of BO .
Some authors found that BO could be triggered by lower respiratory tract infections. In fact, it has been demonstrated that patients who present with respiratory syncytial or parainfluenza virus infection have an increased risk of developing BO in the year following HSCT . The presence of a respiratory tract infection may lead to airway inflammation that causes an inappropriate alloimmune reaction.
Diagnosis of Bronchiolitis Obliterans
BOS clinically manifests as dyspnea at rest or on exertion, dry cough or wheezing. In a significant proportion of cases, it is asymptomatic and revealed by screening PFT. Clinical diagnoses of BOS are based on new-onset airflow obstruction identified by spirometry. Because BOS initial symptoms are nonspecific and spirometric findings are not sensitive, most patients are diagnosed when they have severe airway obstruction. PFT is not sensitive, as BOS is a distal airway disease, and bronchiolar obstruction needs to be widespread before FEV1 declines .
Consensus Criteria for diagnosis of bronchiolitis obliterans/bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation
2005 NIH Consensus Criteria 
Proposed modified Consensus Criteria 
All the following should be met:
All the following should be met:
1. FEV1 < 75 % of predicted normal and FEV1/FVC <70 %.
1. FEV1 < 75 % of predicted normal.
2. Either signs of air trapping by PFT (RV >120 % of predicted normal) or signs of air trapping, small airway thickening or bronchiectasis by in- and expiratory HRCT or pathological confirmation of constrictive bronchiolitis.
2. FEV/VC <0.7.
3. Absence of active respiratory tract infection.
3. Evidence of air trapping on HRCT or RV >120 % of predicted normal.
4. In case of lacking histological proof of BO, at least one other distinctive manifestation of cGVHD in an additional organ system is required.
4. Absence of active respiratory tract infection.
5. Presence of active cGVHD in another organ than the lung.
6. Decrease of the FEV1 by at least 10 % since pretransplant.
7. Use of slow vital capacity for calculation of the FEV1/VC ratio.
In addition to PFT, HRCT should be performed. In the case of BOS, it may reveal a mosaic pattern suggestive of air trapping (Fig. 32.1a) that can be accentuated on expiratory cuts. It can also reveal bronchial thickening, bronchiectasis or bronchiolar nodules with a tree-in-bud pattern [5, 29]. Otherwise, HRCT is needed in the initial evaluation of symptomatic patients to eliminate other causes of respiratory symptoms, such as infectious or inflammatory pneumonitis. Its value in the follow-up of a patient diagnosed with BOS is limited unless new respiratory symptoms develop. Finally, a bronchoscopic exam should be performed to rule out infection in the presence of infiltrates at the HRCT. In the case of normal imaging studies, nasal aspirates, sputum stains and cultures are considered sufficient to rule out viral, bacterial or fungal disease .
BOS may also occur after lung transplantation as the result of a chronic graft rejection. Philit et al. have shown very similar clinical, imaging and functional features both in lung transplant and allogeneic HSCT recipients . Thus, the studies in each of these situations contribute to a better understanding of both conditions.
Management of Bronchiolitis Obliterans Syndrome
BOS is a potentially fatal complication. Despite advances in the management of allogeneic HSCT recipients, the survival and treatment of patients with BOS have not improved over the last two decades. The overall survival rates at 2 and 5 years after allogeneic HSCT are respectively 45 and 15 % in patients who develop BOS . The natural history of BOS is variable. Classically, PFT declines with time, and patients develop infectious complications, which can lead to respiratory insufficiency and, eventually, death. Some patients remain stable after the development of airway obstruction, and a minority (20 %) will respond to treatment . Actual management is based on case series and expert opinion. Based on the assumption that BOS is a manifestation of chronic GVHD, current practice involves optimizing or reintroducing immunosuppressive therapy upon a diagnosis of BOS. Some reports suggest that high-dose systemic corticosteroids (1–2 mg/kg) can improve or at least stabilize the FEV1. If BOS develops upon tapering the immunosuppressive therapy, clinicians usually reintroduce the tapered drug in combination with corticosteroids. Some case reports/series suggest other immunosuppressive therapies, such as TNF-receptor blockade, imatinib and extracorporeal photopheresis (ECP), may be efficacious . These therapeutic options need to be studied further. Converging data suggest the ineffectiveness of rituximab for BOS treatment [32, 33].
It is well known that long-term exposure to corticosteroids, even at low doses, leads to significant complications. To minimize the morbidity associated with this treatment, considering the low efficacy of steroids in this setting, some authors have suggested alternative agents with anti-inflammatory properties. The use of topical steroid treatment is supported by two retrospective studies. We reported decreases in dyspnea and improvements in FEV1 in seven patients with new-onset airflow obstruction treated with combined inhaled therapy (budesonide-formeterol) . Bashoura et al. reported stabilization or improvement in FEV1 in 16/17 BOS patients treated 3–6 months with high-dose fluticasone . A recent study suggests bronchodilator responsiveness in BOS patients . This information may support the inhaled combination therapy, including a long-acting bronchodilator and a corticosteroid, over an inhaled corticosteroid alone. The efficacy of azithromycin in the treatment of BOS following allogeneic HSCT is controversial [37, 38]. Finally, the efficacy of montelukast as a corticosteroid-sparing agent in the treatment of chronic GVHD had been suggested in a pilot study . These three agents are actually under study in BOS patients following HSCT, either alone or in combination .
Non Infectious Infiltrative Lung Diseases
Non infectious infiltrative lung diseases (ILDs) occurring late after allogeneic HSCT are not uncommon, representing 12 % to more than 60 % of late-onset non-infectious pulmonary complications in large retrospective studies, including OP [41, 42]. In the largest retrospective studies, ILDs after allogeneic HSCT are mostly described as OP, interstitial pneumonia or idiopathic pneumonia syndrome (IPS) [41, 43, 44]. Whereas OP has been well described in a large study , limited data are available on other forms of infiltrative lung diseases following allogeneic HSCT.
Idiopathic Pneumonia Syndrome
Diagnostic criteria of idiopathic pneumonia syndrome occurring after hematopoietic stem cell transplantation 
1. Evidence of widespread alveolar injury
Multilobar radiologic infiltrates (chest X-ray, computed tomography)
Symptoms and signs of pneumonia (cough, dyspnea, tachypnea, rales)
Evidence of abnormal pulmonary physiology
Increased alveolar to arterial oxygen difference
New or increased restrictive pulmonary function test abnormality
2. Absence of active lower respiratory tract infection
Negativity of exhaustive microbiological assessments of BAL fluid and non-invasive samples (serum, nasal swab, sputum)
Bacteriology, virology, mycology and parasitology
Culture, cytology, direct fluorescence, serology and polymerase chain reaction
Transbronchial biopsy if condition of the patient permits
3. Absence of cardiac dysfunction, acute renal failure, or iatrogenic fluid overload as etiology for pulmonary dysfunction
Conditions routinely included under the classification of idiopathic pneumonia syndrome
Acute interstitial pneumonitis
Acute respiratory distress syndrome
Delayed pulmonary toxicity syndrome
Peri-engraftment respiratory distress syndrome
Noncardiogenic capillary leak syndrome
Diffuse alveolar hemorrhage
The incidence of IPS may vary according to the time following allogeneic HSCT and the type of conditioning regimen, with a historical reported incidence of 3–15 % after myeloablative conditioning, which may be lower (but with a similar severity) after nonmyeloablative conditioning . Although time from allogeneic HSCT is not a diagnostic criterion of this syndrome, IPS occurs early in the course of HSCT (median time: 3–7 weeks after HSCT), with a historical high mortality rate (60–80 %, depending on the study, and up to 90 % in case of respiratory failure requiring mechanical ventilation). Proposed risk factors of IPS include total body irradiation-based myeloablative conditioning regimens, older recipient age, myelodysplastic syndrome, acute leukemia as an underlying disease and acute GVHD . However, the association between IPS and acute GVHD is inconstant in humans, although a causal relationship between the two disorders has been proposed .
Therapeutic strategies for IPS include supportive care measures, broad-spectrum antimicrobial agents and intravenous corticosteroids. However, new treatments are needed due to the lack of efficacy of the currently applied strategies. Etarnercept, a neutralizing agent of TNF-α, is currently being evaluated for this indication and has yielded encouraging results that should be confirmed . In fact, new insights in the classification of IPS that include very different entities would likely lead to better propositions of treatments.
In a case control study, Freudenberger et al. described 49 cases of biopsy-proven OP following allogeneic HSCT and compared them to control subjects from a computerized database of all patients who received an allogeneic transplant . They identified a strong association between OP and previous signs of acute and chronic GVHD, suggesting a causal link between both entities [5, 7]. Other authors have also associated post-allogeneic HSCT OP with the presence of HLA B35 antigen . The time from HSCT to OP onset ranged from a few days to more than 7 years, with a median time of 108 days. In 22 % of these cases, a tapering of immunosuppressive treatments preceded the respiratory signs. The clinical presentation was similar to that of COP, mimicking unresolved or subacute infectious pneumonia with unspecific symptoms (fever, dyspnea and cough) and physical signs (crackles). Radiological signs consisted of alveolar, nodular or interstitial opacities with a focal, multifocal or more diffuse extension that is indicative of the diagnosis when the topography of the lesions is peripheral or peribronchovascular [7, 51, 52] (Fig. 32.2a). Unlike COP, opacities were rarely migratory .
Freudenberger et al. found normal PFT in 38 % of the patients with post-allogeneic HSCT OP, whereas 43 % had a restrictive pattern, 11 % had an obstructive ventilatory defect and 8 % had both. In addition, a decrease in the carbon monoxide diffusion capacity was noted in 64 % of the cases . The histological features of post-allogeneic HSCT OP were similar to the histological pattern of COP. In Freudenberger’s study, almost 80 % of the patients were treated with steroids, with improvement or stabilization in most cases. However, 22 % of the patients progressed, despite a treatment with high-dose corticosteroids, leading to death due to respiratory failure in most cases .
Other Infiltrative Lung Diseases
High-dose steroids were usually administered as the first-line therapy and were often associated with a reinforcement of other immunosuppressive drugs. The survival rate was estimated to be 61 % at 24 months from ILD diagnosis. The main cause of death was respiratory failure . Because late fibrosis often remains inaccessible to conventional therapies, early identification and treatment of ILD are essential for prognosis. For this purpose, ILD should be suspected in every atypical, subacute or unresolved case of infectious pneumonia, especially in the presence of extrathoracic chronic GVHD.
GVHD sometimes has features resembling autoimmune disorders, such as scleroderma, Sjögren syndrome, lupus erythematous, mixed connective tissue disease, polymyositis ANCA-positive vasculitis, or primary biliary cirrhosis. A spectrum of pulmonary manifestations occurring in patients with a well-defined connective tissue disease (CTD) after allogeneic HSCT similar to idiopathic CTD has been reported . Therefore, nonspecific interstitial pneumonia and lymphoid pneumonia have been reported in the course of Sjögren-like disorders diagnosed on both clinical and biological characteristic features . The incidence of these CTDs that may arise very late after allogeneic HSCT remains unknown, and they are most likely overlooked . Several pathologic mechanisms have been proposed for these autoimmune manifestations, such as genetic predisposition, thymic deficiency, the expression of an abnormal B-cell and/or T-cell reconstitution or donor-related pathogenic clone transfer [58, 59]. The prognoses for these ILDs occurring in post-allogeneic HSCT connective tissue disorders are poor with very high mortality rates despite the usual administration of high dose steroids . Considering therapeutic protocols similar to those used in CTD (e.g., cyclophosphamide, anti-CD20 monoclonal antibodies or TNFR blockers) might be interesting in addition or as an alternative to the more classical steroid therapy.
A wide spectrum of lung diseases can be observed in patients treated for hematological malignancies. In addition to infectious causes, various inflammatory conditions may be encountered similar to those observed in other contexts. In the context of allogeneic HSCT, these pulmonary complications are often attributed to GVHD. However, pulmonary GVHD is not a clinical diagnosis; rather, it is only the concept of a pathophysiological process. The elucidation of specific clinical, radiological and histopathological pulmonary entities is necessary to adapt patient care and to improve prognosis.
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