EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Hemoptysis is a symptom that can be caused by airway disease, pulmonary parenchymal disease, or pulmonary vascular disease, or it can be idiopathic. Infection is the most common cause of hemoptysis, accounting for 60% to 70% of cases. Hemoptysis is also an initial symptom of diffuse alveolar hemorrhage syndrome, although it may be absent at presentation in one-third of patients. Diffuse alveolar hemorrhage is characterized by disruption of the alveolar-capillary basement membranes because of either injury or inflammation of the arterioles, venules, or capillaries, resulting in bleeding in alveolar spaces. To date, no study in the literature has investigated the cause of hemoptysis in renal transplant patients. In this retrospective study, we aimed to investigate the causes of hemoptysis in renal recipients.

Materials and Methods: The data included in this study were obtained from 352 renal transplant patients who were consulted by the pulmonology department regarding hemoptysis between 2011 and 2017 at Baskent University. Patient medical records were reviewed for demographic, clinical, radiographic, bronchoscopic features, and microbiology data. Immunosuppressive drugs and clinical outcome data were also noted.

Results: This study included 352 renal transplant patients (139 male patients with mean age of 34.9 ± 7 years and 113 female patients with mean age of 31.1 ± 5 years). Hemoptysis was detected in 17 patients (4.8%),with 3 (0.85%) having massive hemoptysis as a result of diffuse alveolar hemorrhage syndrome. Fourteen of our patient group (4%) had pneumonia, and Aspergillus species was detected in 5 patients (1.4%). The only reason for diffuse alveolar hemorrhage was immunosuppressive agents, including sirolimus and mycophenolate mofetil.

Conclusions: Hemoptysis is an important respiratory symptom in renal transplant patients. Although community- or hospital-acquired pneumonia may result in hemoptysis, drug-induced diffuse alveolar hemorrhage and Aspergillus infection should be considered for causes in renal transplant patients.

Key words : Diagnosis, Hemoptysis, Transplantation

Hemoptysis, expectoration of blood from the tracheobronchial tree, is associated with numerous diseases. The causes of hemoptysis are categorized under airway diseases, pulmonary parenchymal diseases, vascular diseases, coagulation disorders, iatrogenic injuries, and miscellaneous. It is important to evaluate the amount of hemoptysis and to identify the underlying causes. Expectorated volume of blood over a 24-hour period is used to classify hemoptysis as massive or nonmassive bleeding. Massive hemoptysis, a life-threatening condition in which bleeding cannot be cleared from the dead space, has also been defined as more than 600 mL of blood expectorated over 1 day.¹ Nonmassive hemoptysis is defined as less than 200 mL of blood expectorated during a 24-hour period.

Anemia, alveolar infiltrates, decreased hemoglobin levels, and respiratory failure can be found clinically according to amount of hemoptysis. Impaired platelet function in patients with renal failure results in increased risk of bleeding, including gastrointestinal bleeding, retinal hemorrhage, hemoptysis, gingival bleeding, subdural hematoma, hemarthrosis, and petechial.^2-4 A hospital-based study found that the risk of bleeding is increased 2-fold in patients with renal failure.⁵ The pathophysiologic basis for the increased risk of bleeding in patients with renal failure and how much this risk of bleeding decreases after renal transplant are unclear. Hemoptysis, a serious clinical condition, has not been investigated for its cause in renal transplant patients as far as we know. In this retrospective study, we investigated the causes of hemoptysis in renal transplant patients.

Materials and Methods

We collected data from medical records of 352 renal transplant patients who were seen at the pulmonology department regarding hemoptysis between 2011 and 2017 at Baskent University. All patients with hemoptysis had been assessed by the consulting pulmonologist at the time of hospital admission; therefore, pseudo-hemoptysis had been already excluded by the consulting doctor. Patient demographic, clinical, laboratory, and microbiology data and radiographic and bronchoscopic features were obtained from the medical records. Immunosuppressive drugs and clinical outcome data were also noted. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21.0, IBM Corporation, Armonk, NY, USA). Descriptive statistics are presented as means and standard deviation, median (minimum to maximum), frequency distribution, and percent.

The study included 352 renal transplantation patients (139 male and 113 female) with mean age of 33.9 ± 7 years. We found 17 renal transplantation patients (4.8%) who developed hemoptysis from follow-up data. Pneumonia was the leading cause of hemoptysis, with 4% (14 patients) in the study group. The microbiologic agent was Aspergillus species in 5/14 patients (35.7%), whereas any causative agent was not obtained in the other 9 patients (64%). The other causes of hemoptysis included drug-induced diffuse alveolar hemorrhage (DAH) caused by sirolimus and mycophenolate mofetil (MMF) in 3 patients (0.85%) (Table 1). Massive hemoptysis was detected in 3 patients: 2 with drug-induced DAH and 1 with invasive pulmonary aspergillosis. The 4 patient deaths in our study group were attributed to pneumonia.

Characteristics of renal transplant patients with hemoptysis are presented in Table 2. There were 12 male and 5 female patients with mean age of 33 ± 5 years. Regarding smoking, 10 of 17 patients were never-smokers, 5 patients had smoked more than 10 packs/year, and 2 patients reported a history of less than 10 packs/year. The causes of renal failure were vesicourethral reflux, hypertension, unknown cause, pyelonephritis, systemic lupus erythematous, membranoproliferative glomerulonephritis, diabetes mellitus, Alport syndrome, and Buerger disease.

Hemoptysis is an important symptom, creating anxiety for both the clinician and the patient based on the amount of hemoptysis found clinically. Fortunately, it is self-limiting in most cases, with less than 5% of patients having severe or massive bleeding.⁶ The blood supply of the lung originates from the pulmonary and bronchial arterial system. Small vessels usually cause focal or diffuse hemorrhage due to immunologic, vasculitic, cardiovascular, and coagulation-related causes, whereas hemoptysis originating from large vessels is due to infection, cardiovascular, congenital, neoplastic, and vasculitic diseases.⁷

Diffuse alveolar hemorrhage is characterized by hemoptysis, anemia, and diffuse pulmonary infiltrates on radiologic examination. In solid-organ transplant patients, DAH may occur secondary to infection or drug reaction. Infection is the most common cause of hemoptysis, found in nearly 60% to 70% of all cases.⁸ Hemoptysis is mostly associated with lung abscess, fungal pneumonia, necrotizing pneumonia, and tuberculous and nontuberculous mycobacterial diseases.^9-11

In our study, we found 14 renal transplant patients who developed hemoptysis secondary to infection. We documented that pneumonia found in 5 of 14 patients was caused by Aspergillus infection. Aspergillus fumigatus was the most common isolated pathogen in our study group. Invasive pulmonary aspergillosis has been reported to occur in approximately 0.7% and in up to 4% of renal transplant patients.^12-14 The difference between the literature and our study population could be explained by differences in environmental exposure in the patients.

Invasive pulmonary aspergillosis causes massive and life-threatening hemoptysis in 40% to 60% of patients.¹⁰ In our study, all pneumonia patients, except for one who had invasive pulmonary aspergillosis, developed nonmassive and self-limiting hemoptysis. Fiberoptic bronchoscopy (FB) was performed within the first 48 hours in these patients, and antifungal agents were administered empirically after the procedure. We suggest that an early decision to perform FB and empiric treatment initiation for fungus could decrease the poor effects of invasive pulmonary aspergillosis on bronchial arterial vessels.

Fiberoptic bronchoscopy was performed in 8 (57%) of the 14 renal transplant patients with pneumonia. One study suggested that, when an initial episode of nonmassive hemoptysis occurs, the presence of an infiltrate combined with signs and symptoms consistent with pneumonia may require only antibiotics and repeated radiography to ensure resolution of the infiltrate and no evaluation by FB.¹⁵ On the basis of this perspective, FB should be considered when it is necessary to obtain the causative pathogen of infection. To our knowledges, with high-resolution computed tomography, the appearance of pulmonary hemorrhage is variable and not specific for a particular cause. In addition, the amount of hemoptysis may not reflect the actual bleeding in some cases. However, despite early imaging features, hemoptysis is a life-threatening clinical condition that should be treated without delay.¹⁶ For these reasons, we believe that FB and bronchoalveolar lavage should both be performed to detect the side of bleeding and to allow discovery of the underlying cause in all renal transplant patients with hemoptysis.

Diffuse alveolar hemorrhage has been described to be related to viruses (including cytomegalovirus, human immunodeficiency, Epstein-Barr, and type 1 human T-cell lymphotrophic infections), Mycoplasma species, fungi (invasive pulmonary aspergillosis, Candida species, and Pneumocystis jiroveci), bacterial pneumonia (Legionella pneumoniae, Stenotrophomonas maltophilia), and mycobacteria (Mycobacterium tuberculosis)^17-20 in immunosuppressed patients. Early sputum and bronchoalveolar lavage of patients who had these tests did not yield the causative pathogens other than Aspergillus. This result could be attributed to FB not performed in all of the 14 patients in our study. The diagnostic yield of bronchoscopy ranges from 30% to 72% and is highest when performed for pulmonary opacities within the first 6 months of transplant.^21-28

The history of the patient frequently guides the clinician to investigate other causes of hemoptysis besides infection. The diagnosis of pulmonary drug toxicity begins with suspicion in transplant patients who have new or progressive respiratory symptoms, including hemoptysis and dyspnea. Certain immunosuppressive drugs used to prevent organ rejection have been described to lead to DAH.¹⁹ We found 3 patients had drug-induced DAH, 1 who received sirolimus and 2 who received MMF for maintenance of immunosuppression. Withdrawal of these drugs resulted in improvement of hemoptysis and pulmonary infiltrates in a few months. Sirolimus, an inhibitor of the mammalian target of rapamycin, was reported previously as cause for DAH in a renal transplant patient.²⁹ Mycophenolate mofetil, a newly developed immunosuppressive agent that inhibits T-cell and B-cell proliferation by blocking the production of guanosine nucleotides, was described in the literature as a cause of hemoptysis and pulmonary infiltrates on postoperative day 1 of a renal transplant recipient.³⁰ There are some reports regarding mammalian targets of rapamycin being associated with drug-induced interstitial pneumonitis, fibrosing alveolitis, and pulmonary hemorrhage after renal transplant, and mechanisms are not clear whether this association is a direct or immuno-mediated toxicity.^31,32 The literature is scarce about the pulmonary effects of MMF, including its role in DAH. It remains unclear whether MMF-induced pulmonary pathology lay along with its better known side effects or is a unique condition that occurs itself.

Some reports have suggested that the adverse effects of sirolimus are dose dependent; however, a few patients who had sirolimus trough concentrations lower than previously shown toxic levels still developed pulmonary toxicity.³³ Therapeutic MMF monitoring in renal transplant has not yet been clarified.³⁴ Dose reduction and discontinuation of the drug are major treatment recommendations for drug-induced DAH.⁷ We preferred an immunosuppressive drug change in our patients who had drug-induced hemoptysis. We need to share our experiences more about the pulmonary adverse effects of these immunosuppressive drugs.

A tendency to bleed has been reported in patients with chronic renal failure.^3,4 Insufficient platelet function related to composition of α-granules, impaired binding of platelets to the vessel wall, and drug interactions between platelets and uremic toxins resulting in a reduced adhesion and aggregation of platelets can increase the risk of bleeding in patients with chronic renal failure.^34,35 Nine patients in our study group had organ rejection and required hemodialysis again. We could not deny enhanced impairment of renal function as the cause of increased bleeding risk and dysfunctional hemostasis in our patients; however, hemodialysis has been shown to improve platelet abnormality due to removal of uremic toxins.³⁶

When renal transplant patients present with hemoptysis and pulmonary infiltrates, clinicians should consider infectious and noninfectious causes, mainly pneumonia, including pulmonary aspergillosis, and drug-induced DAH. We suggest that FB and bronchoalveolar lavage should be performed to differentiate the underlying cause and to avoid delayed treatment.

Volume: 16 Issue: 1 March 2018 - Supplement - 1

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