Abstract
Non-malignant late effects after hematopoietic stem cell transplantation (HSCT) are heterogeneous in nature and intensity. The type and severity of the late complications depend on the type of transplantation and the conditioning regimen applied. Based on the most recent knowledge, we discuss three typical non-malignant complications in long-term survivors after HSCT, namely pulmonary, cardiovascular and renal complications. These complications illustrate perfectly the great diversity in respect of frequency, time of appearance, risk factors, and outcome. Respiratory tract complications are frequent, appear usually within the first two years, are closely related to chronic graft-versus-host disease (GVHD) and are often of poor prognosis. Cardiac and cardiovascular complications are mainly related to cardiotoxic chemotherapy and total body irradiation, and to the increase of cardiovascular risk factors. They appear very late after HSCT, with a low magnitude of risk during the first decade. However, their incidence might increase significantly with longer follow-up. The chronic kidney diseases are usually asymptomatic until end stage disease, occur within the first decade after HSCT, and are mainly related with the use of nephrotoxic drugs such as calcineurin inhibitors. We will discuss the practical screening recommendations that could assist practitioner in the follow-up of long-term survivors after HSCT.
Late complications are conditions appearing after the early phase of hematopoietic stem cell transplantation (HSCT) with clinical consequences on the long-term survivorship. Depending on the type of complication, the threshold between early and late might be set at different time points. Some of the complications with relevant late consequences can start as early as 3 months after HSCT, and other events will become apparent only years or even decades later. Here, we define as late complications all events occurring beyond 3 months (Figure 1), and separate them into delayed (3 months to 2 years), late (2 to 10 years) and very late events (>10 years). Late complications after HSCT are the consequence of the conditioning regimen, chronic graft-versus-host disease (GVHD) and its treatment, infectious complications, the treatments used before transplantation, and the pretransplant comorbidity. Many late complications, such as secondary cancer, cataracts, infertility, endocrine dysfunctions, or late bone and joint complications, have been well described. In theory, any organ can be the target of a late effect, and frequently multiple causes are involved. This review will focus on late pulmonary, cardiac and cardiovascular as well as renal consequences after HSCT. It will consider the involved risk factors and the recommended screening practices (Table 1).
Clinical manifestations, risk factors and interventions in pulmonary, cardiac, cardiovascular and renal late complications after hematopoietic stem cell transplantation (HSCT).
Sequence of appearance of pulmonary, cardiac, cardiovascular and renal complications after hematopoietic stem cell transplantation (HSCT), and main risk factors. Late complications are subdivided into delayed events (between 3 months and 2 years), late events (between 2 and 10 years), and very late events (> 10 years).
Delayed onset pulmonary complications involving both the airway and lung parenchyma are frequent after HSCT. They include infectious complications in immunocompromised hosts and noninfectious complications of the lung. The most common noninfectious late complications include bronchiolitis obliterans (BO), bronchiolitis obliterans organizing pneumonia (BOOP), and idiopathic pneumonia syndrome (IPS).1 BOOP/COP has also been termed cryptogenic organizing pneumonia (COP) in order to avoid confusion with airway diseases such as bronchiolitic obliterans syndrome (BOS).2 These pulmonary complications, belonging to the delayed events, appear usually within 3 months to 2 years after HSCT. However, the functional consequences often persist for years after HSCT. There are differences between autologous and allogeneic HSCT, particularly in respect of time of appearance. In autologous but not in allogeneic HSCT, pulmonary complications are unusual after 3 months. In a retrospective analysis, the 2-year cumulative incidence of delayed onset noninfectious pulmonary complications was 10% among 438 patients surviving more than 3 months, and 15.6% among those with chronic GVHD.3 The 5-year overall survival was significantly worse in patients with a pulmonary complication, compared to those without. In the unrelated HSCT setting, the incidence of delayed onset noninfectious pulmonary complications is higher and the clinical outcome of these patients worse.4 Chronic extensive GVHD and advanced-stage disease is associated with the development of delayed onset pulmonary complications.
Restrictive and obstructive ventilatory defects and gas transfer abnormalities are common after HSCT. A decrease in forced expiratory volume in 1 second (FEV1) and the FEV1/forced vital capacity (FVC) ratio is the hallmark of airflow obstruction. Restrictive defects are measured by the total lung capacity (TLC) and may be associated with impaired diffusing capacity for carbon monoxide (DLCO). Pulmonary function evaluated retrospectively in 69 patients with a minimum of 5-year follow-up after allogeneic HSCT showed a late decrease from baseline in 31 (45%) of the patients, with a restrictive pattern in 25, and an obstructive pattern in 6. Twelve of the 31 (38%) patients with abnormal pulmonary function were symptomatic.5 Abnormal pulmonary function before transplantation and chronic GVHD were independently associated with late decrease in pulmonary function compared with baseline. In children, a significant proportion have abnormal function tests after HSCT.6 They involve mainly abnormalities of DLCO and TLC, implying restrictive lung disease and diffusion abnormalities. Obstructive abnormalities are less frequently observed. In a prospective study of the Late Effects Working Party of the EBMT, cumulative incidence of lung impairment evaluated in 162 children by pulmonary function was 35% at 5 years. Chronic GVHD was the major risk factor for reduced lung function. In most children the deterioration of pulmonary function was asymptomatic.7
Bronchiolitis obliterans is a severe pulmonary manifestation characterized by a nonspecific inflammatory injury affecting primarily the small airways. At the initial stage, it is typically an obstructive respiratory disease (Figure 2A/ 2B; see Color Figures, page 495). At a more advanced stage, due to the progressive peribronchiolar fibrosis, BO often presents obstructive and restrictive functional changes. The incidence of BO varies widely in different reports, ranging between 0 and 48%. Among 2152 allogeneic HSCT recipients reported in 9 studies the incidence of BO was 8.3%.8 BO is strongly associated with chronic GVHD, suggesting that BO is a pulmonary manifestation of chronic GVHD.9 However, despite the fact that BO rarely develops in patients without GVHD, single cases of BO have been reported after autologous HSCT. Following peripheral blood progenitor cell transplantation patients were shown to have a 3-fold increase in the risk of BO compared with those who had bone marrow transplantation.10 Other potential risk factors include the use of methotrexate for GVHD prophylaxis, older age of the recipient and/or the donor, busulfan-based myeloablative conditioning, antecedent respiratory viral infection, and low levels of serum immunoglobulin.
The presentation of BO is usually insidious, with a median onset approximately 1 year post-HSCT. The main symptoms are dry cough, progressive dyspnea, and wheezing. Fever does usually not occur, unless there is a concomitant infection. Asymptomatic presentation with abnormal functional tests is observed in 20% of the cases. In the early stage chest X-ray is normal; thus, the presence of parenchymal changes suggests an infection or an unrelated process. In more advanced phases, evidence of hyperinflation may be found. High resolution computed tomography (HRCT) of the chest with inspiratory and expiratory images is the radiological procedure of choice to assess the structural changes in the lung with suspected BO. Pulmonary lobules with normal airways increase their density during expiration, while areas with obstructed airways and air trapping remain radiolucent. This provides a characteristic mosaic image that is highly suggestive of BO. The sensitivity to detect air trapping for the diagnosis of BO ranges between 74% and 91% and specificity between 67% and 94%.1113 The predictive negative value is higher than 90%. Hence, when no air trapping is seen on expiratory HRCT the diagnosis of BO is very unlikely. At the early stage, pulmonary function tests show air flow obstruction with decreased FEV1, normal TLC and DLCO. A > 20% decline in FEV1 from the pretransplant value, or < 80% of the predicted FEV1 should alert clinicians. Recently, an international workshop on chronic GVHD by the National Institutes of Health defined biopsy-proven BO as the only diagnostic criteria of chronic GVHD in the lung (Figure 2C; see Color Figures, page 495). BO is clinically diagnosed when the following conditions are met: (1) FEV1/FVC ratio < 0.7 and FEV1 < 75% of predicted value; (2) evidence of air trapping or small airway thickening or bronchiectasis in HRCT; and (3) absence of infection in the respiratory tract.14
There are no prospective clinical trials on the treatment of BO. So far, the therapeutical recommendations are mainly derived from retrospective studies and from expert opinion.8,15,16 The management is based on the treatment of chronic GVHD. Early detection and prompt immunosuppressive treatment are likely to contribute to a more favorable outcome. Inhaled corticosteroids with bronchodilatator have shown some utility in the management of obstructive airway disease after HSCT.17,18 Further treatment consists of high-dose, systemic corticosteroids and the institution or augmentation of immunosuppressive therapy. Corticosteroids in a dose of 1 to 2 mg/kg/day for 2 to 6 weeks remain the mainstay of the treatment. Higher doses of corticosteroids have not shown higher efficacy. Cyclosporine is often used concomitantly. The addition of a third immunosuppressive agent such as azathioprine, thalidomide, anti-thymocyte globulin, anti TNF-, or the use of macrolide antibiotics have been shown to be beneficial in some cases. Prevention of Pneumocystis jirovecii and the early treatment of superinfection is an important component of the treatment strategy. However, prognosis of patients with BO remains poor, and mortality remains high. In a majority of cases, death is attributed to progressive respiratory failure or opportunistic infections.
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Late Pulmonary, Cardiovascular, and Renal Complications ...