EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Bronchiectasis, Computed tomography scan, Solid-organ transplant

Bronchiectasis is a congenital or an acquired anatomic disorder characterized by permanent and irreversible abnormal dilatation of the bronchi.¹ It is a disease with increasing prevalence, causing significant clinical and economic burden.² Congenital, anatomical, or systemic diseases, bronchial obstructive chronic conditions (foreign body, lymph node), and previous lung infections may cause bronchiectasis.^3,4 Several studies have reported that bronchiectasis can develop in children and adults after renal transplant, and the use of immunosuppressive drugs plays a role in its etiology.^5,11 However, there are limited data on the development of bronchiectasis after other solid-organ transplants, such as heart and liver.¹²

The most feared complication after solid-organ transplant is acute and chronic rejection. The main immunosuppressive drugs used to control allograft rejection include corticosteroids, calcineurin inhibitors (cyclosporine A, tacrolimus), T- and B-cell proliferation inhibitors, and mycophenolate mofetil (MMF). Common side effects of immunosuppressive drugs include increased susceptibility to all infections, especially lung infections.⁵ This study was undertaken to determine the incidence of bronchiectasis after solid-organ transplant, to analyze the characteristics of cases with bronchiectasis, and to evaluate potential relationships.

Materials and Methods

In our retrospective study, clinical, radiological, and laboratory data of patients who underwent solid-organ transplant (liver, kidney, and heart) at the Ankara Baskent University General Surgery Clinic and Cardiovascular Surgery Clinic between 2003 and 2023 were evaluated. Thoracic computed tomography images were evaluated by expert pulmonologist and chest radiologist, and patients with bronchiectasis were identified (Figure 1).

All solid-organ transplant patients aged 18 years and older were included in the study. Patients were followed for at least 3 years. Patients with bronchiectasis diagnosed before transplant, without computed tomography scan, and with incomplete clinical data were excluded from the study. Data were analyzed retrospectively via the hospital information system, image archiving, and com-munication system common imaging interface and the Republic of Turkey Ministry of Health personal health record system and the Republic of Turkey Ministry of Health teleradiology system.

Thorax computed tomography scan

Each computed tomography scan was reviewed by a pulmonologist and a chest radiologist. Slices 1 to 5 mm thick were analyzed at 5- to 10-mm intervals from the lung apex to the lung bases. The diagnosis of bronchiectasis was defined as an inner diameter of the airway lumen larger than the accompanying pulmonary artery diameter, narrowing of the bronchi, and imaging of the bronchi within 1 cm of the pleural surface.¹³

Ethical considerations

This study was approved by the Baskent University Institutional Review Board (No. KA22/276) and supported by Baskent University Research Fund. All of the protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Statistical analyses

We analyzed the distribution of study parameters among the groups by using the Kolmogorov-Smirnov test. Variables were defined as median (minimum-maximum [range]) and percentage. We used the Mann-Whitney U test or the Kruskal Wallis test to compare variables showing nonhomogeneous distribution. Categorical variables between groups were compared by the Pearson chi-square test or the Fisher exact test.

Univariate and multivariate logistic regression analyses were performed to determinate the risk factors affecting bronchiectasis and pneumonia. P < .05 was considered significant. We used SPSS version 23.0 (SPSS Inc) for statistical analyses.

The median age of 468 transplant patients included in the study was 45 years (range, 16-76 y), and 67.7% were male. The median age at transplant was 36 years (range, 10-67 y). Kidney transplant was performed in 61.5% (n = 207), heart transplant in 20.3% (n = 95), and liver transplant in 18.2% (n = 85) of patients. In our study group, 50.2% of transplants were from living donors, of which 42.5% (n = 100) were first-degree relatives and 24.2% (n = 57) were second-degree relatives. Spouses were donors for 47 patients. When the posttransplant treatment scheme was reviewed, 441 patients (94.2%) used a combination of prednisolone, tacrolimus, and MMF. The mortality rate in transplant patients was 17.9% (n = 84). Table 1 and Table 2 list patient demographic data.

Development of pneumonia was significantly less (7.1%) in liver transplant patients compared with other solid-organ transplant groups (P = .042). Pneumonia development time was shorter in heart transplant patients and longer in kidney transplant patients (P = .004). Recurrent pneumonia and bronc-hiectasis were more common in kidney transplant patients, but these findings were not significant (Table 3).

Patients who developed pneumonia had signi-ficantly higher baseline age and transplant age (P = .023; P = .004). The prevalence of pneumonia was significantly higher in those with comorbidities (P = .003). Patients with hypertension had higher frequency of pneumonia development (P < .001). The most common microorganisms detected in sputum cultures of patients with pneumonia were Streptococcus pneumoniae (n = 12), Klebsiella species (n = 6), Pseudomonas aeruginosa (n = 4), Aspergillus fumigatus (n = 3), Acinetobacter species (n = 3), and Moraxella catarrhalis (n = 3).

Patients who developed bronchiectasis were significantly older (P = .037). The prevalence of development of bronchiectasis was significantly higher in patients with comorbidities (P = .033). Chronic obstructive pulmonary disease (COPD), hypertension, and diabetes were significant risk factors in patients who developed bronchiectasis (P < .001, P = .002, and P = .033, respectively). All patients who developed bronchiectasis (n = 13) used a combination of prednisolone, tacrolimus, and MMF. To date, allograft rejection has not developed in these 13 patients. Table 4 lists characteristics of patients who developed bronchiectasis.

In the univariate logistic regression analysis, age, comorbidity, hypertension or COPD, and previous pneumonia were determined to be risk factors for the development of bronchiectasis. When all possible risk factors from the multivariate analyses were evaluated together, the risk of bronchiectasis was 13.64 times higher (95% CI, 1.1-168.44; P = .042) in those with COPD and 10.08 times higher (95% CI, 1.20-84.58; P = .033) in those with pneumonia (Table 5).

Bronchiectasis is a congenital or an acquired anatomic disorder characterized by permanent dilatation and destruction of the bronchial walls. Recurrent lung infections over the years may result in bronchiectasis. Bronchiectasis can be induced by locally or systemically by a defect in the defense system, as in ciliary dyskinesia.¹⁴ Immunodeficiency syndromes, including immunoglobulin G (IgG), IgM, and IgA deficiency, and recurrent sinopulmonary infections are associated with an increased risk of bronchiectasis.¹⁵ The prevalence of bronchiectasis has been increasing worldwide since 2000. It is an important cause of morbidity and mortality in low-income countries and is more common in low-income countries. It is seen in all age groups, but the highest prevalence of the disease is in older age groups.^16,17 Although bronchiectasis has been shown to develop after renal transplant, the development of bronchiectasis after heart and liver transplant has only been reported in single cases and in pediatric cases.¹² No study, to our knowledge, has reported the development of bronchiectasis after heart and liver transplant. Thus, to our knowledge, our study is the first to evaluate the frequency of bronchiectasis in heart and liver transplants compared with kidney transplant. We detected bronchiectasis development in 13 patients (2.7%) and determined a 13.64-fold risk of developing bronchiectasis in patients with COPD and 10.08-fold risk of developing bronchiectasis in patients with pneumonia by using a multivariate regression analysis in which we evaluated possible risk factors for the development of bronchiectasis after transplant (Table 5).

Immunosuppression from drugs used after transplant predisposes patients to recurrent lung infections and increases the risk of posttransplant bronchiectasis.¹⁸ The incidence of pulmonary infection in renal transplant recipients is 8.8%.¹⁹ In fact, in 6 renal transplant cases who developed bronchiectasis in our study, pneumonia developed beforehand, and 3 recipients had recurrent disease. Infectious complications developing after transplant have been associated with a decrease in mannose-binding protein and immunoglobulin levels, and hypogammaglobulinemia has been shown to develop in bronchiectasis cases in 2 studies.^7,10 In our retrospective study, immunoglobulin levels were only studied in 2 cases, and levels were found to be within the normal range.

Current management of patients in our transplant unit includes a triple immunosuppression regimen consisting of tacrolimus (or another calcineurin inhibitor), MMF (or another antimetabolite), and low-dose prednisolone. Because 94.2% of all our cases and 100% of those who developed bronchiectasis used the triple combination of prednisolone, tacrolimus and MMF, it is difficult to determine the development of bronchiectasis by a specific drug. However, MMF, which is used by most transplant patients, has known pulmonary side effects, such as cough, bronchitis, and shortness of breath. Case-based studies have also reported that MMF causes acute respiratory failure through pulmonary fibrosis and pneumonitis.^20,21 There is an association between the development of bronchiectasis and the use of immunosuppressive drugs, especially MMF, in renal transplant patients.^6-10 In a case of colitis caused by MMF, intestinal villus atrophy was shown to be responsible for this condition.²² Based on this information, MMF may lead to the development of bronchiectasis by causing atrophy in the pulmonary epithelial cilia.⁶ Boddana and colleagues reported that MMF causes bronchiectasis through hypogam-maglobulinemia.7Although bronchiectasis was not observed before MMF was added to the immunosup-pressive treatment regimens in previous studies, an increase in bronchiectasis cases was noted after its inclusion in immunosuppressive regimens.^8,9

Polycystin 1 and 2 protein abnormalities in airway cilia and smooth muscles have been shown in patients with autosomal dominant polycystic kidney disease, which is a frequent cause of renal failure and related renal transplant. This structural disorder itself may play a role in the development of bronchiectasis.^10,23 None of our renal transplant recipients who developed bronchiectasis had autosomal dominant polycystic kidney disease.

Bronchiectasis after liver transplant has been shown to develop in pediatric cases.⁸ Bronchiectasis developed in only 1 of our 85 liver transplant patients. The development of bronchiectasis after heart transplant has also been only reported in a single case report.¹² We observed bronchiectasis in 5 of our 95 cases who underwent heart transplant. When the risk factors that could explain the etiology in these patients were examined, no significant finding was found for our liver transplant patients. However, posttransplant pneumonia developed in 3 of 5 heart transplant recipients with bronchiectasis. When the characteristics of our cases who developed bronchiectasis were analyzed, the mean time to bronchiectasis development was 35 months (Table 3); bronchiectasis was shown to develop over a longer time compared with other studies.6,7 All of our patients with bronchiectasis received a combination of prednisolone, tacrolimus, and MMF in im-munosuppressive therapy. Only 3 of our patients had a history of pulmonary disease (COPD) (Table 4).

The most important limitation of our study is its retrospective design. In addition, subgroup analysis for causal variables could not be performed in some patients who developed bronchiectasis, since immunoglobulin levels to elucidate the etiology were not studied.

The pathophysiology of transplant-associated bronc-hiectasis has not yet been clarified. The survival of transplant patients has increased significantly as a result of developments in surgical techniques and im-munosuppressive drugs after solid-organ transplant. However, side effects related to immunosuppressive drugs continue to be observed. The fact that there may be more than 1 causal factor in the majority of bronchiectasis cases reported after transplant cannot be excluded, as underlying diseases, recurrent pulmonary infections, and potential effects from immunosuppressive drugs may contribute to the pathogenesis of bronchiectasis.

The diagnosis of bronchiectasis should be considered in solid-organ transplant recipients who develop cough, abnormal sputum symptoms, and frequently recurrent respiratory tract infections. Patients should receive high-resolution computed tomography scans of the thorax. Further prospective studies are needed to include long-term health outcomes in transplant patients with and without bronchiectasis.

Volume: 22 Issue: 4 April 2024

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