Abstract
Hematopoietic stem cell transplantation (HSCT) is an established therapeutic modality for a number of malignant and nonmalignant conditions. Pulmonary complications following HSCT are associated with increased mortality and morbidity. These complications may be classified into infectious versus noninfectious, and early versus late based on the time of occurrence post-transplant. Thus, exclusion of infectious etiologies is the first step in the diagnoses of pulmonary complications. Late onset noninfectious pulmonary complications typically occur 3 months post-transplant. Bronchiolitis obliterans is the major contributor to late-onset pulmonary complications, and its clinical presentation, pathogenesis, and current therapeutic approaches are discussed. Idiopathic pneumonia syndrome is another important complication which usually occurs early, although its onset may be delayed. Organizing pneumonia is important to recognize due to its responsiveness to corticosteroids. Other late onset noninfectious pulmonary complications discussed here include pulmonary venoocclusive disease, pulmonary cytolytic thrombi, pleuroparenchymal fibroelastosis, thoracic air leak syndrome, and posttransplant lymphoproliferative disorders.
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Keywords
- Bronchiolitis obliterans
- Hematopoietic stem cell transplant
- Pulmonary complications
- Organizing pneumonia
Introduction
Hematopoietic stem cell transplantation (HSCT) is an established form of therapy for a number of malignant as well as nonmalignant conditions. More than 21,000 HSCTs were conducted in the United States in 2016 (https://www.cibmtr.org). The two main types of HSCTs are autologous and allogenic. Autologous HSCT involves collection of stem cells from the patient that are then infused back after chemotherapy. Allogenic HSCT involves infusion of stem cells from a donor.
The morbidity and mortality from HSCT-related complications have been on the decline over the past several years. These complications are broadly categorized based on etiology, namely, whether they are infectious or noninfectious, and the time of onset of such complications, early vs. late. Pulmonary complications are the most common life-threatening complications post HSCT occurring in 30–60% of patients [1]. We define late onset complications are occurring 3 months after post-HSCT (Fig. 1). In this chapter, we discuss late noninfectious pulmonary complications in HSCT, and current concepts on their pathogenesis, diagnosis, and management. The primary focus will be on bronchiolitis obliterans (BO) which is the most common and carries the highest mortality of the late onset noninfectious complications [81]. The other late onset noninfectious complications that will be discussed include idiopathic pneumonia syndrome, organizing pneumonia, pulmonary venoocclusive disease, pulmonary cytolytic thrombi, pleuroparenchymal fibroelastosis, thoracic air leak syndrome, and posttransplant lymphoproliferative disorders.
Timeline of noninfectious HSCT pulmonary complications. BO/BOS bronchiolitis obliterans/bronchiolitis obliterans syndrome, IPS idiopathic pneumonia syndrome, OP organizing pneumonia, PVOD pulmonary venoocclusive disease, PCT pulmonary cytolytic thrombi, PPFE pleuroparenchymal fibroelastosis, TALS thoracic air leak syndrome, PTLD post-transplant lymphoproliferative disorder
Bronchiolitis Obliterans
BO typically occurs between 3 months to several years post HSCT and is inclusive of the spectrum of chronic graft versus host disease (cGVHD) [29, 60]. BO is characterized by progressive, irreversible airway narrowing due to circumferential small airway fibrosis. There is limited understanding of BO pathogenesis. BO is a pathological diagnosis requiring invasive surgical lung biopsy, which is uncommonly performed in the clinical setting. BO syndrome (BOS) is a more useful clinical diagnosis that is made based on irreversible airflow limitation on pulmonary function testing (PFT) without the need for lung biopsy.
BO is the most common late onset noninfectious complication of HSCT. The reported incidence of BO/BOS after allogeneic HSCT varies based on the diagnostic criteria used, ranging from 2% to 30% in retrospective studies [60]. A recent prospective study to evaluate the epidemiology of late non onset noninfectious complications after allogenic stem cell transplant reported a cumulative incidence of BOS 36 months posttransplant at 10.7% [9]. BO/BOS following autologous HSCT is rare but has been reported [31, 61].
Clinical Features and Diagnosis
Clinical features of BO/BOS are nonspecific. In early stages of the disease, patients are asymptomatic and are identified by airflow limitation on PFTs. Nonproductive cough, dyspnea on exertion, and decreased exercise tolerance are common [14]. Physical examination may be normal or reveal signs of airflow obstruction such as wheezing, hyperinflation, or diffuse crackles. Other causes of such presentations, in particular, respiratory infections, should be ruled out.
The chest radiograph may be normal or reveal hyperinflation. High resolution chest tomography (HRCT) reveals small airway involvement with features of air trapping evidenced by mosaic attenuation on expiratory views (Fig. 2). Histopathology, when available, shows narrowing or complete occlusion of the bronchiolar lumen due to subepithelial inflammatory fibrosis is a hallmark of BO (Fig. 3) [5]. Transbronchial biopsies are insufficient to yield a diagnosis and surgical lung biopsies often prohibitively expose patients to procedural risks. In most cases, BOS can be diagnosed without a histopathological diagnosis using PFTs in the appropriate clinical setting.
62-year-old woman with history of allogenic bone marrow transplant for diffuse large B-cell lymphoma 2.5 years back. She presented with progressive shortness of breath. High Resolution Computed Tomography (HRCT) images in inspiration (top row) show subtle mosaic abnormalities (white circles) and the images in expiration (bottom row) show decreased attenuation of these areas (black circles), consistent with air trapping. This appearance is highly concerning for bronchiolitis obliterans syndrome in this setting. (Image courtesy: Dr. Sushilkumar Sonvane, MD – University of Alabama at Birmingham, Department of Radiology)
High power view demonstrating early lesion in bronchiolitis obliterans (a) with peribronchial fibrosis and inflammation progressing to frank interalveolar fibroblastic plug formation (b). (Image courtesy: Dr. David Ralph Crowe, MD – University of Alabama Birmingham, Department of Pathology)
The updated National Institutes of Health (NIH) guidelines for diagnosing BOS are based on the following criteria [43]:
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1.
Forced expiratory volume in one second (FEV1)/vital capacity <0.7 or the fifth percentile of predicted.
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(a)
Vital capacity includes forced vital capacity or slow vital capacity, whichever is greater.
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(b)
The fifth percentile of predicted is the lower limit of the 90% confidence interval.
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(c)
For pediatric or elderly patients, use the lower limits of normal, defined according to National Health and Nutrition Examination Survey III calculations [36].
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(a)
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2.
FEV1 <75% of predicted with ≥10% decline over less than 2 years. FEV1 should not correct to >75% of predicted with albuterol, and the absolute decline for the corrected values should still remain at ≥10% over 2 years.
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3.
Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, computed tomographic (CT) scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, bronchoalveolar lavage).
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4.
One of the two supporting features of BOS:
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(a)
Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT or
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(b)
Evidence of air trapping by PFTs: residual volume >120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence interval
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(a)
It is important to recognize that a significant number of bronchioles must be involved to manifest airflow limitation on PFTs or to develop clinical symptoms. Hence, early stages of BO may be missed.
Risk Factors and Pathogenesis
Several risk factors for the development of BOS have been identified, and most of these are closely associated with the occurrence of cGVHD [98]. Increasing age of the donor/recipient, development of acute GVHD [26], ABO incompatibility [24], the presence of extra thoracic GVHD, low circulating IgG, and non-Caucasian race [4] have been identified in several retrospective studies. Additional risk factors include the type of transplant procedure such a peripheral blood stem cell transplant [57] and busulfan-based conditioning regimens [69]. Use of antithymocyte globulin (ATG) as part of the pretransplant conditioning regimen is associated with a decreased incidence of BOS [22].
Prior to meeting established criteria for BOS, a decrease in FEV1 from pretransplant levels has also been identified to be a risk factor for the subsequent development of BOS [13]. More recently, a 10% decline in FEV1 from pretransplant to day 100 posttransplant has shown to be predictive for the development of BOS [9].
The precise pathogenetic mechanisms involved in the development of BO are unclear. The pathogenesis appears to be multifactorial and may involve diverse etiologies [5]. Airway epithelial injury is the inciting factor secondary to gastroesophageal reflux disease, respiratory infections, and chemotherapeutic drugs. This is typically followed by a dysregulated immune response that leads to the development of fibrotic changes in small airways. T cells and humoral mechanisms have been implicated [23, 76]. Genetic polymorphisms in NOD2/CARD15 have been linked to susceptibility to BOS [39].
Treatment
There are currently no effective treatments for BOS complicating HSCT. Most treatment protocols are based on combinations of immunosuppressive drugs and, until recently, were largely based on expert opinion. Traditionally, immunosuppression in the form of systemic steroids for extended periods has been used; alternatively, calcineurin inhibitors and azathioprine, agents that impair lymphocyte activation and proliferation, have been employed. Long-term, high-intensity immunosuppression is no longer recommended due to the increased risk of infections [91].
Most clinical studies of treatments for BOS are difficult to interpret due to small sample sizes, their retrospective nature, and confounding effects of treatment for cGVHD. These studies have included systemic corticosteroids [28, 65, 82], rituximab [10, 46], imatinib [59], etanercept [12, 95], as well as extracorporeal photopheresis [52]. A recent retrospective matched cohort study recently showed that extracorporeal photopheresis improves survival in HSCT patients with BOS [37].
Treatment with inhaled budesonide/formoterol led to significant FEV1 improvements in patients with mild/severe BOS after allogeneic HSCT [7]. Another trial showed FEV1 stabilization using a combination of fluticasone, azithromycin, and montelukast along with pulse dosed systemic steroids [92]. A randomized, double-blinded, placebo-controlled trial of azithromycin alone did not reveal any change in FEV1 in late BOS post HSCT [48]. Prophylactic azithromycin has been shown to prevent the onset of lung transplant–related BOS, as well as stabilize FEVI in post-lung transplant BOS [19, 88]. However, prophylactic azithromycin has not shown to be effective in BOS post-HSCT in retrospective studies [44]. A prospective study on the prophylactic use of azithromycin to prevent airflow decline resulted in early termination secondary to hematological relapses [8]; an FDA warning was issued in August 2018 until further review (https://www.fda.gov/Drugs/DrugSafety/ucm614085.htm). Prospective trials of azithromycin, bortezomib, inhaled cyclosporine, and neutrophil elastase inhibitors for prophylaxis and/or treatment of BOS are underway (www.clinicaltrials.gov).
Current treatment strategies include high-dose inhaled glucocorticoid with or without a long acting inhaled beta agonist based on symptoms, with close monitoring of lung function with PFTs. If progressive decline in FEV1 occurs with this regimen, initiation of a combination of fluticasone, azithromycin, and montelukast (FAM) therapy can be considered [91]. Occasionally, patients with chronic GVHD and refractory BOS may respond to increased immunosuppression. In patients who progress despite medical therapies, lung transplantation may be the only option [40, 86].
Novel therapeutic approaches for BO/BOS are currently being investigated. The pleiotropic small molecule p38 MAK inhibitor, pirfenidone, has been shown to ameliorate BO in a murine model of cGVHD [25]. An early phase clinical study evaluating the safety and tolerability of pirfenidone in BOS is currently underway (www.clinicaltrials.gov; NCT03315741).
Clinical Course and Prognosis
The clinical course of BOS is variable, with some patients experiencing rapid declines in lung function, while others stabilize or improve. Mortality from BOS is most commonly due to progressive respiratory failure. BOS confers a 1.6 fold increased risk of death after diagnosis [4]. Early onset of BOS and lower FVC, especially within a year of transplant, is associated with a worse prognosis [13, 26]. Recent estimates indicate a 2–3 year survival of 60–75%, and a 5-year survival of 40–50%; this is an improvement in overall survival from a decade ago, when 2-year survival was 40%, and 5-year survival was 20%. Early recognition, newer treatment strategies, and better supportive care likely account for this improved survival [91].
Idiopathic Pneumonia Syndrome
Idiopathic pneumonia syndrome (IPS) is a severe noninfectious complication of HSCT with an incidence of 12% when it was first described in the 1990s; more recently, incidence is cited at 3–15% [14, 60]. IPS is more common as an early complication of HSCT but can occur after 3 months. Median time of onset is 19 days posttransplant, with a range from 4 to 106 days [60]. IPS is an acute lung injury process characterized by diffuse alveolar damage in the absence of an identifiable lower respiratory tract infection.
Pathogenesis and Risk Factors
Although the exact cause of IPS remains unknown, immune involvement has been invoked; murine models involving immune mismatches between donor and recipient support this concept [15, 73]. Elevated levels of lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-α) have been observed in BAL samples of murine IPS models [16]. TNF-α may contribute to pathogenesis by direct toxicity, upregulation of major histocompatibility complex (MHC), increased leukocyte recruitment, and cell-mediated apoptosis [60]. Donor T lymphocytes secrete chemokines which further amplify the inflammatory cascade [38]. Decreased level of pulmonary surfactant has also been associated with IPS development [27, 56, 94].
Risk factors for IPS include full-intensity conditioning regimens such as total body irradiation and busulfan, acute GVHD, advanced age, and underlying acute leukemia and myelodysplastic syndrome (MDS) [33, 68, 90]. Reduced-intensity conditioning regimens have decreased the incidence of IPS [33]. In children, risk factors for IPS include the underlying disease and busulfan-based conditioning regimens [66]. Interestingly, risk of IPS increases with the number of platelet transfusions received, though the transfusion requirement could be a marker of disease severity [84, 85].
Clinical Features and Diagnosis
The definition of IPS, updated in the 2011 American Thoracic Society guidelines, is based on the following criteria [60]:
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1.
Evidence of widespread alveolar injury
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(a)
Multilobar infiltrates on routine chest radiographs or computed tomography
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(b)
Symptoms and signs of pneumonia (cough, dyspnea, tachypnea, rales)
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(c)
Evidence of abnormal pulmonary physiology
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(i)
Increased alveolar to arterial oxygen difference
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(ii)
New or increased restrictive pulmonary function test abnormality
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(i)
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(a)
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2.
Absence of active lower respiratory tract infection based upon:
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(a)
Bronchoalveolar lavage negative for significant bacterial pathogens including acid-fast bacilli, Nocardia, and Legionella species
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(b)
Bronchoalveolar lavage negative for pathogenic nonbacterial microorganisms:
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(i)
Routine culture for viruses and fungi
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(ii)
Shell vial culture for CMV and respiratory RSV
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(iii)
Cytology for CMV inclusions, fungi, and Pneumocystis jirovecii (carinii)
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(iv)
Direct fluorescence staining with antibodies against CMV, RSV, HSV, VZV, influenza virus, parainfluenza virus, adenovirus, and other organisms
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(i)
-
(c)
Other organisms/tests to also consider:
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(i)
Polymerase chain reaction for human metapneumovirus, rhinovirus, coronavirus, and HHV6
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(ii)
Polymerase chain reaction for Chlamydia, Mycoplasma, and Aspergillus species
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(iii)
Serum galactomannan ELISA for Aspergillus species
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(i)
-
(d)
Transbronchial biopsy if condition of the patient permits
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(a)
-
3.
Absence of cardiac dysfunction, acute renal failure, or iatrogenic fluid overload as etiology for pulmonary dysfunction
Radiographic findings can be nonspecific, but HRCT findings include ground glass opacities that are bilateral, central, symmetric, with consolidation seen in more severe cases [75]. Recent advances in diagnostic capabilities have increased detection of occult infections which help separate IPS from infectious HSCT complications; the distinction is critical due to their vastly distinct treatment approaches. Many patients diagnosed with IPS were later discovered to have detectable pathogens, most commonly HHV-6, human rhinovirus, and aspergillus, when their BAL samples were re-examined [72].
Treatment
Historically, treatment of IPS has been largely supportive. Once infections have been ruled out, systemic corticosteroids are the mainstay of treatment; IPS in association with diffuse alveolar hemorrhage may require higher doses [60]. The results of other immunotherapeutic agents such as the soluble TNF-α inhibitor, etanercept, has been mixed. A retrospective single-center study over two distinct time-periods comparing steroids alone (earlier time-period) versus combined steroids and etanercept showed significant improvement in survival to hospital discharge [80]. However, the more recent use of reduced-intensity conditioning regimens and improved supportive care may have accounted for this improvement. Patients with late-onset IPS who responded to etanercept have greatly improved short- and long-term mortality [79]. Results in children have been similarly promising, with complete response in 20% of patients [97]. A randomized, double-blind, placebo-controlled trial comparing corticosteroids with placebo to corticosteroids with etanercept was inconclusive due to slow patient accrual and early termination [96]. Other potential therapies are under investigation. Blockade of NF-κB, a transcription factor downstream of the TNF-α receptor, has shown promise in murine models [30]. Pulmonary surfactant replacement is also being studied as an intervention to treat IPS [60].
Clinical Course and Prognosis
Outcomes for IPS remain poor, with mortality rates between 60% and 80%. Rapid clinical deterioration can occur and >95% of patients requiring mechanical ventilation succumb to the disease [20, 33, 45]. Veno-venous extracorporeal membrane oxygenation (ECMO) as a rescue therapy or bridge-to-recovery has met with mixed results [47, 51]. Short-term survival has improved with treatment advances, but 2-year survival remains low. Based on a small study, a more rapid peak and decline in severity of infiltrates on HRCT has been linked to a more favorable prognosis [75]. Biomarkers to predict patients who at risk for IPS and who respond to biologic therapy are being studied [71].
Organizing Pneumonia
Organizing Pneumonia (OP), formerly known as bronchiolitis organizing pneumonia (BOOP), is a complication of HSCT. It can occur as a part of the IPS spectrum or as a stand-alone late onset pulmonary complication of HSCT [6]. OP as a complication of HSCT was first described by Thirman et al. in 1992 [78]. Although it has been described as a complication of both autologous and allogenic HSCT, it is more common following the latter. The incidence of OP post-allogenic HSCT ranges from 0.9% to 10.3% with a median time of onset post-HSCT of 108 days [74]. Among 5340 patients, who underwent allogenic HSCT, 49 cases of histological BOOP/OP was reported, an incidence of 0.9% [32].
Clinical Features and Diagnosis
OP presents with fever, nonproductive cough, and dyspnea and can be precipitated by a recent taper of immunosuppressive regimen. PFTs commonly reveal a restrictive pattern, but could be normal, obstructive, or mixed with a decreased diffusion capacity of carbon monoxide (DLCO) [32, 58]. High resolution chest tomographic scans in patients with OP are notable for airspace consolidations, ground glass opacities, and nodular opacities (Fig. 4) [50]. In a study of 16 patients with biopsy-proven OP post-HSCT, ground glass opacities were noted to be the most common radiological feature [63]. Bronchoalveolar lavage is useful to exclude infections. Surgical lung biopsy is the gold standard for diagnosis of OP, as transbronchial biopsies have lower yield; however, the latter approach may be useful in certain clinical settings [2, 64]. Histopathological features on biopsy include presence of the buds of granulation tissue which contain myofibroblasts and a loose connective tissue (Fig. 5). These buds are intra-alveolar and can extend into the bronchioles causing obstruction with associated mild interstitial inflammation [18].
69-year-old man with history of bone marrow transplant for AML a few years back. He presented with cough and increased shortness of breath. Noncontrast Computed Tomography (CT) of chest (top row) showed patchy consolidations scattered in peribronchiolar (arrow), perilobular distribution (circle), and peripheral, wedge shaped distribution (arrowhead) that were concerning for atypical infection or organizing pneumonia. The patient underwent bronchoscopy with biopsy. No infectious etiology was identified and a provisional diagnosis of cryptogenic organizing pneumonia was made. Patient was started on steroids and showed symptomatic improvement. Follow-up chest CT scan performed after 2 months (bottom row) showed marked improvement in parenchymal consolidations. (Image courtesy: Dr. Sushilkumar Sonvane, MD – University of Alabama at Birmingham, Department of Radiology)
OP demonstrating fibroblastic plugs are interalveolar at first and are then incorporated into alveolar septa before being resorbed. (Image courtesy: Dr. David Ralph Crowe, MD – University of Alabama at Birmingham, Department of Pathology)
Risk Factors and Pathogenesis
A prior history of acute or chronic GVHD was found to be a strong risk factor for OP [32] and suggests a common pathogenesis. In a study of 9550 patients of post-allogenic HCST recipients, HLA disparity, female-to-male HSCT, and peripheral blood stem cell transplant (PBSCT) were associated with an increased risk of developing OP. In contrast, busulfan-based or fludarabine-based reduced-intensity conditioning compared to total body irradiation and T cell depletion regimens were associated with a lower risk [58]. The precise pathogenetic mechanisms of post-HSCT OP are unclear. The association with GVHD and increased incidence post-allogeneic HSCT suggests alloimmune-mediated lung injury. Murine models of OP after respiratory reovirus infections have demonstrated the role of T cells and cytokines such as interferon-α in the development of the process [53].
Treatment
HSCT-associated OP, as in most other cases of OP, is primarily treated with high-dose systemic corticosteroids. There are no specific guidelines on the dose and duration of steroid therapy. Current recommendations are based on expert opinion, and clinical judgment should be exercised. Prednisone in doses ranging from 0.75–1.5 mg/kg/day have been used for 1–3 months with a slow taper over 6–12 months [17]. Further studies are needed to establish ideal doses and duration of corticosteroid therapy. Erythromycin in combination with corticosteroids has been reported with favorable outcomes [42], although the role of macrolides for treatment of OP is unclear.
Clinical Course and Prognosis
About 80% of patients with HSCT-associated OP have a favorable prognosis with resolution or stabilization after corticosteroid therapy [1]. Clinical improvement is seen usually within a week of starting therapy followed by radiological improvement. Failure to respond to treatment may result in progressive respiratory failure and death [32].
Pulmonary Venocclusive Disease
Pulmonary venoocclusive disease (PVOD) resulting in pulmonary hypertension is a rare late onset complication of both autologous and allogeneic HSCT [98]. In reported cases, it was noted in patients less than 25 years old and presented several weeks to months posttransplant [11].
Clinical Features, Pathogenesis, and Diagnosis
Presenting complaints are usually nonspecific, primarily fatigue and exertional dyspnea. Physical examination findings are similar to those of pulmonary hypertension which may be normal in early stages and become more apparent in later stages: Elevated JVD, peripheral edema, and hepatomegaly. Elevated second heart sound, parasternal lift and palpable second heart sounds in the second left intercostal space can be recognized in some patients along with tricuspid regurgitation murmur. Computed tomographic (CT) scans of the chest may show septal thickening, diffuse or mosaic ground glass opacities, small nodules, and areas of consolidation. Right heart catheterization reveals an increased pulmonary artery pressure and normal pulmonary capillary pressure. The triad of severe pulmonary hypertension in the setting of normal pulmonary artery occlusion pressure and radiographic evidence of pulmonary edema could be suggestive of PVOD but is not diagnostic. PVOD can be definitively diagnosed only by surgical biopsy and is characterized by the progressive intimal proliferation, fibrosis, and occlusion of the pulmonary venules as well as small veins [54]. The pathogenesis of PVOD post HSCT is unclear and has been attributed to toxic endothelial injury secondary to chemotherapeutic conditioning regimens and/or viral infections [74] but does not seem to be associated with cGVHD [6].
Treatment and Prognosis
There are no effective treatments for PVOD and prognosis is poor. Conventional arterial vasodilator therapy for pulmonary hypertension could worsen pulmonary edema in PVOD and if initiated should be done with close monitoring [11, 74]. Reported cases of PVOD post HSCT have shown some favorable response to steroid therapy [11, 35, 41].
Pulmonary Cytolytic Thrombi
Pulmonary cytolytic thrombi (PCT) is a complication of allogenic HSCT and primarily occurs in children with GVHD [93]. The incidence is between 1.2% and 4% with a median onset of 3 months post HSCT [83]. Patients typically present with fever, cough, and dyspnea. CT scans of the chest shows peripheral pulmonary and pleural nodules [93]. Bronchoalveolar lavage is indicated to exclude infectious etiology. The diagnosis of PCT is based on surgical biopsy of the lung nodules which are characterized by vascular occlusive and hemorrhagic infarcts secondary to thrombi containing intensely basophilic amorphous material as well as entrapped leucocytes [34]. The prognosis of PCT is favorable as it responds to treatment with systemic corticosteroids. There has not been any mortality attributed to PCT in the reported literature.
Pleuroparenchymal Fibroelastosis
Pleuroparenchymal fibroelastosis (PPFE) is a rare complication of HSCT, grouped under rare interstitial pneumonias with a prevalence of around 0.3% in HSCT recipients [55]. It is characterized by progressive sub pleural fibrosis predominantly in the upper lobes. PPFE has been reported post allogeneic and autologous HSCT. The etiology of PPFE post HSCT is unclear. Chemotherapeutic drugs, radiation therapy and a possible association with cGVHD have been hypothesized [87] to be predisposing factors.
Patients can present with dry cough, exertional dyspnea, and chest pain secondary to spontaneous pneumothorax [89]. PFTs reveal a restrictive or mixed picture of obstruction and restriction. CT scan is characteristic of pleural thickening, fibrosis, subpleural reticulations, and traction bronchiectasis predominantly in the upper lobes [55]. Histopathological exam reveals alveolar collapse, subpleural fibrosis, and extensive elastic deposition [87]. The disease is progressive with worsening symptoms and poor prognosis. Currently no therapeutic options are available except for lung transplantation [6].
Thoracic Air Leak Syndrome
Thoracic air leak syndrome (TALS) consists of a spectrum of conditions that includes spontaneous pneumothorax, subcutaneous emphysema, pneumomediastinum, interstitial emphysema, and pneumopericardium. It occurs as a late onset complication of allogenic HSCT and is associated with cGVHD. According to reported literature, prevalence of TALS post allogenic HSCT is reported to be 0.83–5.7% with a median time range of 202–575 days post HSCT [6]. The mechanism of air leak in BOS is secondary to increased intra-alveolar pressure leading to alveolar rupture into the pulmonary interstitium with subsequent retrograde dissection of air into the mediastinum and subcutaneous tissue causing pneumomediastinum and subcutaneous emphysema. Similarly, rupture into the pleural space causes pneumothorax [62]. CT scan of the chest is the imaging modality of choice and can detect air in the pleural space, mediastinum, and subcutaneous tissue. Infections, cough, emesis, and other causes of a similar presentation should be ruled out. Prognosis is poor with 1-year and 3-year survival of 45% and 15%, respectively [67].
Post-transplant Lymphoproliferative Disorder
Post-transplant lymphoproliferative disorder (PTLD) is a rare complication following allogeneic HSCT and has a cumulative incidence of 1% [21]. In a study of 21,686 HSCT patients’ risk factors such as unrelated or HLA mismatched donors, use of ATG or monoclonal antibodies against T cells for GVHD prophylaxis or treatment, T cell depleted donor marrow, age >50 years and second HSCT were identified. The incidence of PTLD ranged from 0.2% in patients with no risk factors to more than 8% with more than 3 risk factors [49]. The pathogenesis of post HSCT PTLD is attributed to proliferation of donor Epstein–Barr Virus (EBV) infected B cells in the setting of weakened T-cell immunity. Though post HSCT is common in the lymph nodes, spleen, and liver, pulmonary involvement occurs in about 20% of the cases. Median onset is around 4–6 months post HSCT [3]. Clinical presentation varies and could range from asymptomatic to fulminant tumor lysis syndrome. CT scans of the chest are notable for multiple pulmonary nodules with basal and peripheral predominance, mediastinal and hilar lymphadenopathy, patchy consolidation, pleural effusion, and chest wall or pleural-based masses [70]. Diagnosis may require a biopsy or could be made via noninvasive methods in the appropriate clinical setting. A probable diagnosis is made by increased EBV DNA levels in the setting of lymphadenopathy or hepatosplenomegaly and when other causes have been ruled out, proven disease requires a biopsy. Treatment strategies include rituximab, reduction of immunosuppression, donor lymphocyte infusion, chemotherapy, and EBV-specific cytotoxic T lymphocyte infusions [77]. The prognosis of PTLD post HSCT is poor compared to that occurring after solid organ transplantation [62].
Conclusion
Late onset pulmonary complications following HSCT are a major cause of mortality and morbidity. Advances in transplant techniques, earlier diagnosis, prevention, and management of infectious complications have led to better outcomes as well as shifted the focus to late noninfectious pulmonary complications in HSCT. These complications are myriad and require further studies to develop more effective screening, preventative, and treatment strategies .
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Dsouza, K., Pywell, C., Thannickal, V.J. (2020). Late Noninfectious Pulmonary Complications in Hematopoietic Stem Cell Transplantation. In: Nates, J., Price, K. (eds) Oncologic Critical Care. Springer, Cham. https://doi.org/10.1007/978-3-319-74588-6_51
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