sirolimus and Lung-Diseases--Interstitial

Patients with common variable immunodeficiency (CVID) have a high frequency of inflammatory complications like autoimmune cytopenias, interstitial lung disease and enteropathy. These patients have poor prognosis and effective, timely, and safe treatment of inflammatory complications in CVID is essential, but guidelines and consensus on therapy are often lacking.. This review will focus on current medical treatment of inflammatory complications in CVID and point out some future perspectives based on literature indexed in PubMed. There are a number of good observational studies and case reports on treatment of specific complications, but randomized controlled trials are scarce.. In clinical practice, the most urgent issues that need to be addressed are the preferred treatment of GLILD, enteropathy and liver disease. Treating the underlying immune dysregulation and immune exhaustion in CVID is an alternative approach that potentially could alleviate these and other organ-specific inflammatory complications. Therapies of potential interest and wider use in CVID include mTOR-inhibitors like sirolimus, JAK-inhibitors like tofacitinib, the monoclonal IL-12/23 antibody ustekinumab, the anti-BAFF antibody belimumab and abatacept. For all inflammatory complications, there is a need for prospective therapeutic trials, preferably randomized controlled trials, and multi-center collaborations with larger cohorts of patients will be essential.

Topics: Common Variable Immunodeficiency; Humans; Lung Diseases, Interstitial; Sirolimus

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Doxycycline; Enzyme Inhibitors; Humans; Idiopathic Pulmonary Fibrosis; Immunosuppressive Agents; Indoles; Lung Diseases, Interstitial; Lymphangioleiomyomatosis; Pyridones; Sarcoidosis, Pulmonary; Sirolimus; Smoking; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha

mTOR (mammalian target of rapamycin) inhibitors sirolimus and everolimus, used as immunosuppressants in solid organ transplantation, may cause severe adverse effects, such as interstitial pneumonitis. INCIDENCE AND CLINICAL PRESENTATION: The estimated incidence of interstitial pneumonitis is 4-11% although it may be higher. Most reported cases have occurred in renal transplant recipients treated with sirolimus. Clinical presentation is heterogeneous, which makes diagnosis difficult. Abnormalities, such as ground glass opacities, are often found in computerised axial tomography scans of the chest. Physiopathology is not well-known. However, patients with abnormal renal function and those with previous calcineurin inhibitor treatment display a higher incidence. The relationship between pneumonitis and mTOR inhibitor plasma concentrations is not well defined.. Drug discontinuation and administration of high doses of corticosteroids seems to be an effective treatment. mTOR inhibitor dose reduction and replacing sirolimus with everolimus are other alternatives, but they are still under discussion.. Iatrogenic pneumonitis must be suspected when a transplant recipient being treated with mTOR inhibitors presents respiratory symptoms. There is lack of conclusive data on treatment strategies. It appears that everolimus may be tolerated better than sirolimus.

Topics: Everolimus; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Sirolimus; TOR Serine-Threonine Kinases

We experienced a case of interstitial lung disease (ILD) that occurred one year after the start of everolimus therapy for renal cell carcinoma. The pathological features included interstitial pneumonia with granuloma formation. Everolimus is known to cause ILD; however, its pathology is unclear. Granuloma-forming interstitial pneumonia associated with everolimus is uncommon, although it may be one of the pathological patterns associated with everolimus-induced ILD. This is a slow-onset case of everolimus-induced ILD in a patient with renal cell carcinoma. Physicians should thus be aware of the potential for the development of ILD at any time during the administration of everolimus therapy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Granuloma, Respiratory Tract; Humans; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Time Factors

Mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving proliferation, cell survival, and angiogenesis. These pathways are frequently abnormally regulated in cancer. Notably, Akt is an upstream molecule which is over-expressed and/or activated in several cancers. Therefore, mTOR inhibitors can be options for the treatment of cancers. At present, mTOR inhibitors are applied to treat patients with metastatic renal cell carcinoma (RCC). Temsirolimus is indicated as the first line therapy for RCC patients with poor prognosis, whereas everolimus as the second line for those refractory to sorafenib or sunitinib. Interstitial pneumonia is the most serious adverse event for both agents. Clinical trials are under way to explore indications for various cancers.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Proliferation; Cell Survival; Clinical Trials as Topic; Everolimus; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Lung Diseases, Interstitial; Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses various environmental stimuli in most cells primarily to control cell growth. Restriction of cellular proliferation by mTOR inhibition led to the use of mTOR inhibitors as immunosuppressants in allogeneic transplantation as well as novel anticancer agents. However, distinct inflammatory side effects such as fever, pneumonitis, glomerulonephritis or anemia of chronic disease have been observed under this treatment regime. Apart from the mere cell-cycle regulatory effect of mTOR in dividing cells, recent data revealed a master regulatory role of mTOR in the innate immune system. Hence, inhibition of mTOR promotes proinflammatory cytokines such as IL-12 and IL-1beta, inhibits the anti-inflammatory cytokine IL-10 and boosts MHC antigen presentation via autophagy in monocytes/macrophages and dendritic cells. Moreover, mTOR regulates type I interferon production and the expression of chemokine receptors and costimulatory molecules. These results place mTOR in a complex immunoregulatory context by controlling innate and adaptive immune responses. In this review, we discuss the clinical consequences of mTOR-inhibitor therapy and aim to integrate this recent data into our current view of the molecular mechanisms of clinically employed mTOR inhibitors and discuss their relevance with special emphasis to transplantation.

Topics: Animals; Autophagy; Cell Cycle; Dendritic Cells; Humans; Immunity, Innate; Intercellular Adhesion Molecule-1; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural; Lung Diseases, Interstitial; Macrophages; Mice; Protein Serine-Threonine Kinases; Rats; Reperfusion Injury; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

As our understanding of the pathobiology and natural history of the various forms of interstitial lung disease (ILD) has evolved, so have our approaches to treating this heterogeneous group of lung disorders. The earliest pharmacologic agents used to treat various forms of ILD were corticosteroids, and corticosteroids are currently the mainstay of therapy for many forms of ILD. However, it has become clear that corticosteroids and other anti-inflammatory agents lack efficacy for many forms of ILD, such as idiopathic pulmonary fibrosis (IPF), and newer therapies that are in clinical trials target the fibrogenic process and/or secondary pulmonary hypertension (PH) that is present in various forms of fibrotic lung disease. Novel therapies, such as the use of biologic agents (antibodies and cell cycle inhibitors) or stem cell therapies will undoubtedly evolve as new research is performed and clinical trials are undertaken. Lung transplantation remains an option for advanced lung disease that is progressive and unresponsive to non-surgical therapies.

Topics: Clinical Trials as Topic; Cyclophosphamide; Glucocorticoids; Humans; Idiopathic Pulmonary Fibrosis; Immunosuppressive Agents; Lung Diseases, Interstitial; Macrolides; Risk Assessment; Sarcoidosis, Pulmonary; Sirolimus

Sirolimus-associated pulmonary disease should be considered in the differential diagnosis of acute respiratory distress syndrome in transplant recipients receiving this drug. It represents a rare, potentially lethal, and yet reversible adverse effect. We report the case an infant who presented with acute respiratory distress 57 days after heart transplantation 3 days after starting sirolimus. The acute presentation and prompt resolution after discontinuation of this drug suggest a direct toxic effect to the lungs. To our knowledge, this is the first published pediatric description of this syndrome after heart transplantation.

Topics: Acute Disease; Chylothorax; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Lung Diseases, Interstitial; Radiography, Thoracic; Respiratory Insufficiency; Sirolimus

Sirolimus is a potent immunosuppressive drug that began to be used in the last few years. This drug was initially used in renal transplantation but its use in other solid organ transplantations such as liver, heart, lung and pancreas, has been increasing. Sirolimus is indicated in rescue therapies and to reduce the secondary toxic effects of calcineurin inhibitors. However, this drug has been associated with infrequent but severe pulmonary toxicity and cases of interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and alveolar proteinosis have been described. We present the case of a male liver transplant recipient who developed interstitial pneumonitis associated with sirolimus use.

Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus

Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature.. We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases.. Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks.. The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung; Lung Diseases, Interstitial; Middle Aged; Sirolimus; Time Factors

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The use of inhibitors of the mammalian target of rapamycin (mTORi) in renal transplantation is associated with many side effects, the potentially most severe being interstitial pneumonitis. Several papers have reported on sirolimus-induced pneumonitis, but less is published on everolimus-induced pneumonitis (EIP). Data on risk factors for contracting EIP are even more scarce. In the present case-cohort study in renal transplant recipients (RTR), we aimed to assess the incidence and risk factors of EIP after renal transplantation. This study is a retrospective substudy of a multicenter randomized controlled trial. All patients included in the original trial and treated with prednisolone/everolimus were included in this substudy. RTR who developed EIP were identified as cases. RTR without pulmonary symptoms served as controls. Thirteen of 102 patients (12.7%) developed EIP. We did not find any predisposing factors, especially no correlation with everolimus concentration. On pulmonary CT scan, EIP presented with an organizing pneumonia-like pattern, a nonspecific interstitial pneumonitis-like pattern, or both. Median time (range) to the development of EIP after start of everolimus was 162 (38-407) days. In conclusion, EIP is common in RTR, presenting with an organizing pneumonia, a nonspecific interstitial pneumonitis-like pattern, or both. No predisposing factors could be identified (Trial registration number: NTR567 (www.trialregister.nl), ISRCTN69188731).

Topics: Adult; Aged; Cohort Studies; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Risk; Sirolimus; Tomography, X-Ray Computed

Pulmonary Lymphangioleiomyomatosis (LAM) is a rare disease of the lung and lymphatic system that primarily affects women of childbearing age. LAM is a progressive disease with a terrible prognosis, which worsens over time and is extremely difficult to treat. In this study, we discuss the case of a 31-year-old woman with LAM who was initially misdiagnosed with leiomyoma and the way that led to a true diagnosis and effective treatment. Following a precise diagnosis based on comprehensive clinical data and particular immunohistochemical tests, sirolimus treatment was initiated, and the patient entirely responded to the treatment. This case report demonstrated that LAM is an uncommon condition that is challenging to diagnose, which causes its treatment to be delayed.

Topics: Adult; Female; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphangioleiomyomatosis; Sirolimus

A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan.. Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks).. Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1).. The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Japan; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Sirolimus; Treatment Outcome

Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a potent immunosuppressant that is increasingly used in prevention and treatment of graft-vs-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) patients. However, data regarding its adverse effects in HSCT patients remain limited. We describe an 18-year-old HSCT patient with a history of invasive fungal infection, who developed pericardial effusion with cardiac tamponade and interstitial pneumonitis while receiving sirolimus for GVHD prophylaxis. Our case illustrates potentially life-threatening complications of sirolimus use in allogeneic HSCT patients.

Topics: Adolescent; Cardiac Tamponade; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Mycoses; Pericardial Effusion; Postoperative Complications; Recurrence; Siblings; Sirolimus

One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success.. Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs).. A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects.. These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

Topics: Abnormalities, Multiple; Adolescent; Biomarkers; Child; Face; Female; Hematologic Diseases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Sirolimus; T-Lymphocytes, Regulatory; Vestibular Diseases

Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.

Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cell Culture Techniques; Cell Differentiation; Cell Movement; Cell Proliferation; Epithelial Cells; Hepatocyte Growth Factor; Hippo Signaling Pathway; Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Membrane Proteins; Oncogene Protein v-akt; Organogenesis; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; PTEN Phosphohydrolase; Ribosomal Protein S6 Kinases; Serine-Threonine Kinase 3; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Tumor Suppressor Proteins; Verteporfin; YAP-Signaling Proteins

Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has been reported as a potential cause.. Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry).. We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii) and 14 cases of ILD (53.8%) resulted as drug-induced ILD (DI-ILD). According to anti-rejection protocols, DI-ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVL(TLC)) and cyclosporine (2nd-hour concentration: CyA(C2)) levels were higher than in patients in the same regimen but with ILD- (EVL(TLC) [ng/mL] 9.84 versus 6.85; CyA(C2) [ng/mL] 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVL(TLC) + CyA(C2)/100) resulted in a significant difference between groups of patients (12.88 ± 1.61 versus 9.83 ± 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 (P = .0081) and 0.9082 (P = .0028), respectively, when using EVL(TLC) or the combination formula with both drugs.. In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVL(TLC) is >9.03 ng/mL or >11.41 when a formula with summation of EVL(TLC) and CyA(C2) is used.

Topics: Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases, Interstitial; Male; Postoperative Complications; Predictive Value of Tests; Retrospective Studies; ROC Curve; Sirolimus

Pulmonary toxicity has frequently been recognized as a potentially serious complication associated with sirolimus therapy. It consists of a wide spectrum of syndromes most characterized by the presence of lymphocytic alveolitis and lymphocytic interstitial pneumonitis. The most commonly presenting symptoms are fever and dyspnea. Chest computed tomography generally reveals bilateral, patchy, or diffuse alveolointerstitial infiltrates. The discontinuation or dose reduction of sirolimus usually leads in most cases to a good outcome with complete clinical and radiologic resolution. However, to establish a diagnosis is difficult because of the absence of specific diagnostic criteria, and in rare cases, it could be fatal or life threatening when the diagnosis was delayed. Here, we reported 2 severe cases of acute respiratory distress attributed to the therapy of sirolimus in solid organ transplant recipients. Although the diagnostic course was difficult, withdrawal of sirolimus and temporary administration of steroids eventually resulted in a rapid recovery in both 2 patients. In addition, possible mechanisms, clinical characteristics, approach to diagnosis, and treatment strategies of sirolimus-induced pulmonary toxicity were also discussed in this article.

Topics: Acute Disease; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Tomography, X-Ray Computed; Transplant Recipients

Sirolimus-induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus-induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus-induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus-induced pulmonary toxicity in children after HCT have been reported.

Topics: Child; Humans; Hypoxia; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Male; Polycythemia; Radiography, Thoracic; Respiratory Function Tests; Sirolimus; Stem Cell Transplantation

A 55-year-old Japanese man was admitted to Oita University Hospital (Oita, Japan) for pyrexia, malaise and dyspnea, and abnormal shadows on chest radiographs. He had started receiving sunitinib (37.5 mg a day for 3 weeks, followed by a 3-week break before beginning the next dosing cycle) for metastatic renal cell carcinoma after the improvement of temsirolimus-induced interstitial pneumonia. Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of metastatic renal cell carcinoma, and the most common clinical adverse effects of sunitinib are diarrhea, mucositis, stomatitis, hypertension, rashes and altered taste. We herein report a rare case of sunitinib-related interstitial pneumonia after treatment with temsirolimus for metastatic renal cell carcinoma. This case suggests the possibility of recall phenomenon of drug-induced pneumonia during the administration of additional chemotherapy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Pyrroles; Radiography; Sirolimus; Sunitinib

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Monitoring; Everolimus; Female; Humans; Lung Diseases, Interstitial; Mucin-1; Sirolimus; Treatment Outcome

We report a case of the rechallenge of everolimus for metastatic renal cell carcinoma (RCC) after successful recovery from grade 3 interstitial lung disease (ILD). A 76-year-old man with metastatic RCC developed grade 3 ILD one month after the initiation of everolimus therapy (10 mg/day). ILD subsided in 4 months after the withdrawal of everolimus and treatment with corticosteroids. Half dose (5 mg/day) of everolimus was rechallenged for 9 months until another grade 3 ILD developed. Everolimus kept the disease under control for 13 months including the discontinuation period.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Enzyme Inhibitors; Everolimus; Fatal Outcome; Humans; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Prednisolone; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC). Experiences on ILD-management in mRCC remain limited. mRCC patients treated with everolimus, temsirolimus, or sunitinib at three centres from January 2006 until December 2009 were analysed, retrospectively. Medical records and imaging studies, as well as clinical course, the incidence, diagnostic measures, treatment, and outcome of ILD were assessed. Twenty-six ILD patients (11 %) were identified out of 237 mRCC patients. Median treatment until ILD-diagnosis was 3.8 (range: 1-21.5) months. The ILD-frequency was 2.7 % (n = 6/226) during sunitinib therapy and 19.8 % (n = 20/101) during m-TOR-inhibitor treatment. Cough was the prevailing symptom (69.2 %, n = 18). Bronchoalveolar lavage reviled often lymphocytic (42.9 %, n = 6/14) or eosinophilic cellularity (28.6 %, n = 4/14). Dose reduction (42.3 %, n = 11), treatment interruption (46.2 %, n = 12) or termination (23.1 %, n = 6), and steroid application (34.6 %, n = 9) were common measures in ILD. Interestingly, eosinophilic ILD required pulsed steroids. Improvement occurred in 73.7 % of symptomatic patients. Continuation of targeted therapies was warranted in 65.4 % of ILD patients. No patient died from ILD. ILD during targeted mRCC treatment is common, and supportive measures should be adapted to the clinical course, and potentially in dependence of BAL findings. Re-exposure to targeted therapies appears feasible.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Pyrroles; Retrospective Studies; Risk Factors; Sirolimus; Sunitinib

A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed homogeneous ground-glass opacities with mosaic patterns, especially in the apical region. The laboratory results revealed a decreased white blood cell count with lymphocytopenia and high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was suspected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was thought to be drug-induced interstitial lung disease. However, it was not possible to rule out pneumocystis pneumonia, because the patient was immunocompromised and the computed tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis progressed rapidly and the patient developed respiratory failure, so we performed bronchoalveolar lavage to make a definitive diagnosis, and simultaneously started treatment with prednisolone and trimethoprim-sulfamethoxazole to cover both interstitial lung disease and pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage fluid was positive for Pneumocystis carinii DNA, and the serum level of β-d-glucan was significantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated with everolimus, and interstitial lung disease is the first condition suspected when a patient presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia should be considered as a differential diagnosis when pneumonitis is encountered in patients receiving everolimus therapy.

Topics: Aged; Anti-Infective Agents; Antineoplastic Agents; Bronchoalveolar Lavage; Carcinoma, Renal Cell; Diagnosis, Differential; Drug Administration Schedule; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Neoplasms; Lung Diseases, Interstitial; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Respiratory Insufficiency; Sirolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Chemotherapy-associated interstitial lung disease (ILD) is often fatal, and the chemotherapeutic regimen generally cannot be resumed. ILD associated with the mammalian target of rapamycin (mTOR) inhibitor everolimus has many features distinct from chemotherapy-associated ILD. We present the case of a 58-year-old woman with an advanced pancreatic neuroendocrine tumor with liver metastases, in whom everolimus treatment was maintained and resulted in a partial response despite two occurrences of everolimus-induced ILD during a 31-month treatment period until disease progression. Physicians treating with everolimus should monitor patients closely for ILD and should apply appropriate management strategies to optimize the possibility of maintaining everolimus therapy.

Topics: Antineoplastic Agents; C-Reactive Protein; Everolimus; Female; Humans; Liver Neoplasms; Lung Diseases, Interstitial; Middle Aged; Mucin-1; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; Tomography, X-Ray Computed

The aim of the study was to assess the safety and efficacy of everolimus therapy for advanced renal cell carcinoma in Japanese patients receiving real-world care.. Patients who had been treated with everolimus for advanced renal cell carcinoma at 39 Japanese medical centers between January 2010 and November 2011 were retrospectively investigated to assess adverse events and the time to treatment failure.. A total of 180 patients were identified. Their median age was 65 years (range 23-93). The median time to treatment failure was 2.9 months (95% confidence interval 2.4-3.4). The median time to treatment failure was significantly longer in patients with dose modification (4.2 months; 95% confidence interval 3.4-5.0) than in patients without dose modification (1.7 months; 95% confidence interval 1.0-2.3; P < 0.01) after experiencing adverse events. Stomatitis (44%) was the most frequent adverse event, followed by thrombocytopenia (31%), anemia (22%), interstitial pneumonia (22%) and hyperglycemia (17%). Interstitial pneumonia was the most frequent cause of discontinuation in patients who discontinued everolimus due to intolerability regardless of the dose modification status. None of the patients with dose modification of everolimus discontinued everolimus due to thrombocytopenia or leukopenia.. The adverse event profile of everolimus may differ between Japanese and Caucasian patients. Dose modification of everolimus might be associated with longer treatment duration in patients with advanced renal cell carcinoma. Further studies are required to clarify this association. Interstitial pneumonia may be difficult to overcome by dose modification.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Everolimus; Female; Humans; Hyperglycemia; Japan; Kaplan-Meier Estimate; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Retrospective Studies; Sirolimus; Stomatitis; Thrombocytopenia; Treatment Outcome

Topics: Aged; Anticoagulants; Antitubercular Agents; Comorbidity; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Pericarditis; Phenindione; Polypharmacy; Postoperative Complications; Rifampin; Sirolimus; Venous Thrombosis; Vitamin K

Sirolimus is a powerful immunosuppressive drug which is being used increasingly after liver transplantation because of its renal sparing and anti-tumour effects. It has been associated with uncommon, but potentially fatal, interstitial pneumonitis.. To determine the frequency and outcome of sirolimus-associated pneumonitis following liver transplantation.. Retrospective study in an adult liver transplant centre.. We identified five patients with siromimus-associated pneumonitis, three of whom were transplanted at our centre. Between 1999 and 2008 a total of 522 liver transplants were performed, in our unit, and 45 patients were switched from calcineurin inhibitors to sirolimus. Three of these 45 patients subsequently developed pneumonitis (6.7%). The most common presenting symptoms were cough and dyspnea. The duration of use of sirolimus before diagnosis of pneumonitis varied between 4 and 16 months. Trough serum sirolimus levels were elevated in 3/5 patients with pneumonitis. Sirolimus was withdrawn in all five patients with complete resolution of symptoms and radiological findings.. Pneumonitis is a relatively common side effect of sirolimus in liver transplant patients and can occur despite normal therapeutic blood levels. It is reversible on stopping the medication. Early recognition is important to prevent unnecessary investigations and prolonged morbidity.

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Time Factors; Withholding Treatment; Young Adult

Topics: Biopsy; Bronchiolitis; Cell Count; Cell Proliferation; Female; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Middle Aged; Myocytes, Smooth Muscle; Sirolimus; Treatment Outcome

Sirolimus is a potent immunosuppressive agent used with increasing frequency in kidney transplantation. However, sirolimus can increase the rate of unexplained interstitial pneumonitis. The aim of this study was to evaluate the clinical characteristics of sirolimus-induced pneumonitis and the therapeutic results in renal transplant recipients.. Seventy-two patients received sirolimus, conversion or de novo regimen, at our center between January 2007 and April 2011. Twelve of the 72 patients (16.7%) developed interstitial pneumonitis. The patients were divided into three groups according to the following indications of sirolimus use: de novo, early conversion, and late conversion groups.. The mean duration of follow-up was 11.0 ± 11.5 months. The mean blood level of sirolimus measured by microparticulate enzyme immunoassay was 16.5 ± 7.4 ng/mL at the time of diagnosis. The mean time from the start of sirolimus to pneumonitis onset was 14.7 ± 8.0 months. The clinical presentation included fever, cough, dyspnea, general weakness, and periorbital edema. In most cases, radiological imaging tests revealed bilateral lower-lobe involvement. Bronchoalveolar lavage was performed in three patients and two patients showed lymphocytic alveolitis. Sirolimus was discontinued or reduced for the treatment of pneumonitis. All cases of pneumonitis were resolved within 2 to 4 weeks.. Sirolimus blood level should be monitored tightly and early intervention is important when sirolimus-induced pneumonitis is suspected.

Topics: Adult; Analysis of Variance; Drug Monitoring; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Republic of Korea; Retrospective Studies; Sirolimus; Time Factors; Treatment Outcome

To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease.. Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus.. Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months.. Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

Topics: Aged; Antineoplastic Agents; Biomarkers; Biopsy; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Carcinoma, Renal Cell; Diagnosis, Differential; Disease Progression; Drug Administration Schedule; Everolimus; Female; Humans; Japan; Kidney Neoplasms; L-Lactate Dehydrogenase; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Mucin-1; Pulmonary Surfactants; Severity of Illness Index; Sirolimus; Tomography, X-Ray Computed

Topics: Aged; Coronary Vessels; Drug-Eluting Stents; Everolimus; Humans; Lung Diseases, Interstitial; Male; Sirolimus

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

Topics: Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methotrexate; Middle Aged; Retrospective Studies; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Thrombotic Microangiopathies; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Topics: Animals; Bleomycin; Disease Models, Animal; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Lymphangioleiomyomatosis; Mesenchymal Stem Cell Transplantation; Pulmonary Fibrosis; Sirolimus

We herein report two cases of everolimus-associated interstitial pneumonia in patients with renal cell carcinoma. A 68-year-old Japanese man (case 1) was admitted to our hospital because of progressive dyspnea, left infiltration and consolidation on chest radiographs. He had started receiving everolimus (10 mg daily) three months before the admission for the treatment of recurrent renal cell carcinoma. Bronchoalveolar lavage fluid taken from his left B(4) showed a marked increase of lymphocytes (42.9%). An organizing pneumonia pattern of everolimus-associated interstitial pneumonia was strongly suspected radiologically, and treatment with high-dose corticosteroids, discontinuation of everolimus and oxygen support was started. The treatment was successful, and the patient recovered with only minor pulmonary fibrotic changes in the left lower lobe. A 57-year-old Japanese man (case 2) was referred to our department for the evaluation of interstitial pneumonia. He had started to receive everolimus (10 mg daily) four months previously. Chest CT demonstrated interstitial pneumonia predominantly in bilateral lower lobes, with small pulmonary metastatic nodules. His pulmonary complications were spontaneously resolved eight days after the discontinuation of everolimus. To the best of our knowledge, Case 1 is the first reported case of successfully treated organizing pneumonia pattern of interstitial pneumonia with acute respiratory failure induced by everolimus in Japan.

Topics: Adrenal Cortex Hormones; Aged; Carcinoma, Renal Cell; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Radiography; Respiratory Insufficiency; Sirolimus

Topics: Aged; Everolimus; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Sirolimus

Topics: Aged; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Retrospective Studies; Sirolimus; Spain

Pulmonary toxicity (PT) is emerging as a frequent and serious complication of sirolimus, a proliferation signal inhibitor (PSI) used in solid-organ transplantation. Everolimus is a more recently developed PSI with molecular structure very similar to that of sirolimus. Surprisingly, although experience with everolimus is increasing and becoming substantial, there remains very little information about everolimus-related PT. Herein we report 2 heart transplant recipients who developed a non-infectious pulmonary syndrome after everolimus treatment was started. Transbronchial pulmonary biopsy specimens showed typical interstitial pneumonitis, and everolimus discontinuation resulted in rapid clinical and radiological improvement. Although PT seems to be more common after sirolimus exposure, everolimus is by no means spared from this potentially lethal complication and should always be suspected in the relevant clinical setting.

Topics: Aged; Biopsy; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Treatment Outcome

Inhibitors of mTOR (mammalian target of rapamycin) are immunosuppressants with less nephrotoxic potential than calcineurin inhibitors and antiproliferative effects, which are advantageous in the case of malignancy. However, a series of adverse events has been reported with the first-generation mTOR inhibitor sirolimus that includes hypersensitivity-like interstitial pneumonitis. To our knowledge, only one case of a pneumonitis associated with everolimus in a heart transplant patient has been reported, and it was related to elevated trough blood levels. We report herein the first case of a kidney graft recipient who developed everolimus-associated pneumonitis with normal trough blood levels that was completely reversed after drug withdrawal.

Topics: Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Protein Kinases; Radiography; Sirolimus; TOR Serine-Threonine Kinases

Topics: Biopsy; Diagnosis, Differential; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Radiography, Thoracic; Sirolimus; Tomography, X-Ray Computed

Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)-free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus.. During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months.. After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 +/- 0.6 vs 1.5 +/- 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 +/- 21.6 vs 61.8 +/- 23.4 ml/[min x 1.73 m2], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia (n = 2), skin disorders (n = 2), reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3).. Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients.

Topics: Adult; Aged; Blood Pressure; Everolimus; Female; Fever of Unknown Origin; Follow-Up Studies; Heart Transplantation; Hepatitis B virus; Humans; Immunosuppressive Agents; Kidney; Lipids; Lung Diseases, Interstitial; Male; Middle Aged; Prospective Studies; Sirolimus; Skin Diseases; Time Factors; Virus Activation

Everolimus (Certican; Novartis Pharma AG, Basel, Switzerland) represents the latest generation of proliferation signal inhibitors (PSIs). Everolimus is indicated for use as an immunosuppressive drug in renal and heart transplantation. This report reflects the recommendations of the second German-Austrian Certican Consensus Conference, held in January 2006, for the clinical use of everolimus.

Topics: Angioedema; Coronary Disease; Drug Interactions; Drug Monitoring; Everolimus; Heart Diseases; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Lipids; Lung Diseases, Interstitial; Renal Insufficiency; Sirolimus; Skin Diseases; Transplantation, Homologous; Wound Healing

Topics: Aged; Bronchiolitis Obliterans; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Respiratory Function Tests; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

Sirolimus is an immunosuppressant with expanding use in pediatric organ transplantation, dermatology and rheumatology. We report two cases of children who developed asthma like symptoms and were diagnosed with interstitial lung disease, which responded to discontinuation of sirolimus. Pediatricians should be aware about the pulmonary side effects of sirolimus.

Topics: Asthma; Child, Preschool; Cytomegalovirus Infections; Diagnosis, Differential; Female; Graft Rejection; Hirschsprung Disease; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lung Diseases, Interstitial; Male; Sirolimus

Sirolimus is a powerful immunosuppressive drug initially used in kidney transplant patients but now increasingly employed in recipients of other types of solid organ transplants, such as liver, heart, lung, or pancreas. Sirolimus is indicated for rescue therapy and to reduce the toxic side effects of calcineurin inhibitors. However, its use has been associated with an uncommon but important pulmonary toxicity. Reports have described interstitial pneumonitis, bronchiolitis obliterans, organizing pneumonia, and alveolar proteinosis. We present the case of a liver transplant patient with interstitial pneumonitis associated with sirolimus.

Topics: Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Sirolimus inhibits human fibroblast cell proliferation in cell cultures from transbronchial biopsies of lung transplant recipients. However, a few cases of interstitial pneumonitis and bronchiolitis obliterans organizing pneumonia have been recently described in solid organ transplant recipients, including a fatality in a heart transplant recipient. We studied the patterns of pulmonary adverse effects associated with sirolimus in 4 renal transplant recipients who developed pulmonary opacities on chest radiograph, which were proved to be noninfectious in origin. Lung biopsy was performed to obtain histological diagnosis (3 interstitial pneumonitis, 1 necrotizing vasculitis). Symptoms were dyspnea (4), cough (2), hemoptysis (1), fever (1) and eyelid edema (1). Those with interstitial pneumonitis had bilateral basal opacities on chest X-ray, and histopathology showed mild lymphoplasmocytic interstitial inflammation, scattered intraalveolar epitheloid granulomas and a focal pattern of organizing pneumonia. Serum C-reactive protein (CRP) was elevated and bronchoalveolar lavage revealed lymphocytosis (77, 79.5 and 31%). The fourth patient had an opacity localized in the upper lobe, which progressed to both the lower lobes, and histopathology showed multifocal necroses of lung tissue with lymphoplasmocytic vasculitis and scattered granulomas. In this patient, the serum CRP level was not elevated and bronchoalveolar lavage was normal. Pulmonary symptoms and opacities on chest radiograph resolved and the serum CRP level became normal after sirolimus was stopped in all patients. Sirolimus may be a cause of interstitial pneumonitis or pulmonary vasculitis, and withdrawal of sirolimus is therapeutic.

Topics: Aged; Biopsy; Diagnosis, Differential; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Radiography, Thoracic; Sirolimus

Sirolimus is a new immunosuppressive drug used in organ transplantation, particularly in renal transplantation. In the future, it could replace calcineurin inhibitors such as cyclosporine. It is currently associated with side effects, such as thrombocytopenia and hyperlipidemia. Several interstitial pneumonitis associated with sirolimus has been previously described in renal transplant recipients associated with marked general symptoms.. We report on a 65-year-old renal recipient presenting with a non typical case of sirolimus interstitial pneumonitis. He presented with fever and marked general symptoms for several months. CT scan showed a unilateral interstitial pneumonitis. After infectious, inflammatory and tumoral diseases were ruled out, sirolimus associated interstitial pneumonitis was evoked. The patient improved quickly after discontinuation of sirolimus.. It is important to evoke, after eliminating other aetiologies, sirolimus induced pneumonitis in face of an organ transplant recipient presenting with marked general symptoms even if the pulmonary symptoms are not predominant.

Topics: Aged; Bronchoalveolar Lavage Fluid; Bronchoscopy; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Male; Sirolimus; Tomography, X-Ray Computed

Sirolimus (rapamycin) and everolimus are immunosuppressive agents that inhibit cardiac allograft vasculopathy. Sirolimus has been widely used in renal transplantation, and its use in heart transplantation is increasing. Sirolimus-associated pneumonitis has been described in renal transplant patients. Two cases of sirolimus-associated pneumonitis have been reported after cardiac transplantation. Only 1 case has been described in detail, and this had a fatal outcome. Here, we present a case of sirolimus-associated interstitial pneumonitis in a cardiac transplant recipient that resolved completely with withdrawal of the drug and treatment with corticosteroids.

Topics: Adrenal Cortex Hormones; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Tomography, X-Ray Computed

Topics: Acetylcysteine; Autoantibodies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Lithiasis; Lung Diseases, Interstitial; Pulmonary Alveolar Proteinosis; Pulmonary Alveoli; Sirolimus

Sirolimus-induced interstitial pneumonitis (SIP) has been reported mainly in renal transplant recipients. However, it has recently been reported with increasing frequency in heart transplantation (HT) patients switched from calcineurin inhibitors (CNIs) to sirolimus. We reviewed the medical records of 30 patients who were treated with sirolimus. Twenty-seven patients were switched from a CNI, 2 patients were initially treated with sirolimus and in 1 patient sirolimus was used to treat a persistent cellular acute rejection. Three patients developed SIP. Symptoms included dry cough, shortness of breath and hypoxemia. High-resolution computed tomography (HRCT) scans showed patchy pulmonary consolidation in a peribronchial distribution or diffuse interstitial pulmonary infiltrates. Before onset of SIP, 2 patients had previous heart failure. Sirolimus discontinuation resulted in a complete resolution of symptoms. SIP is a common and severe adverse event (10%) in HT recipients treated with sirolimus. Drug discontinuation can dramatically improve clinical status. Previous lung injury may play a role in SIP pathogenesis.

Topics: Aged; Diagnosis, Differential; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Lung Diseases, Interstitial; Male; Middle Aged; Postoperative Complications; Sirolimus; Tomography, X-Ray Computed

Topics: Aged; Diagnosis, Differential; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Lung Volume Measurements; Male; Postoperative Complications; Sirolimus; Tomography, X-Ray Computed

Sirolimus is a potent immunosuppressive agent used with increasing frequency in solid organ transplantation (SOT). However, it has been associated with rare but devastating pulmonary toxicity. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 64-yr-old heart transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among SOT recipients in an effort to better understand the pathophysiology, risk factors, and outcomes of this rare but serious complication. A total of 64 cases have been reported since January 2000 including the present case. These consisted of 52 kidney, four lung, three liver, three heart, one heart-lung and one islet cell transplants. In most cases, patients presented with a constellation of symptoms consisting of fever, dyspnea, fatigue, cough, and occasionally hemoptysis. Although the risk factors for this association have not been clearly established, high dose, late exposure to the drug and male gender have been noticed among most. In almost all of the reported cases, sirolimus was added later in the course of immunosuppressive therapy, usually in an effort to attenuate the nephrotoxic effects of a previous regimen containing a calcineurin inhibitor. There were three deaths (4.8%) among 62 patients with known status at follow up; all deaths were among heart transplant recipients. Most patients (95%) resolved their clinical and radiographic findings with discontinuation or dose-reduction of the drug. Sirolimus-induced pulmonary toxicity is a rare but serious entity that should be considered in the differential diagnosis of a transplant recipient presenting with respiratory compromise. Dose-reduction or discontinuation of the drug can be life saving.

Topics: Bronchoscopy; Cardiomyopathy, Dilated; Disease Progression; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Sirolimus; Tomography, X-Ray Computed

We report interstitial pneumonitis caused by sirolimus (Rapamune, an immunosuppressive agent) in a renal transplant patient. This rare manifestation was recently recognized as a troublesome adverse effect of sirolimus in many solid-organ transplant recipients, the majority of whom are kidney transplant recipients. While on sirolimus our patient developed cough, fever, and patchy infiltrates, which failed to respond to multiple courses of antibiotic therapy. Biopsy showed findings characteristic of drug-induced hypersensitivity pneumonitis, and excluded other entities, such as opportunistic infection. Improvement occurred only upon discontinuation of the sirolimus.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Radiography; Sirolimus

Topics: Anti-Inflammatory Agents; Body Temperature; Bronchoalveolar Lavage Fluid; Bronchoscopy; Coronary Artery Bypass; Cough; Cyclosporine; Diabetic Nephropathies; Diagnosis, Differential; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Middle Aged; Prednisone; Radiography, Thoracic; Risk Factors; Sirolimus; Tomography, X-Ray Computed; Xenobiotics

Sirolimus is an immunosuppressive drug which has proved its effectivity to reduce the incidence of acute rejection in renal transplantation receptors. As this drug lacks nephrotoxic effects, its simultaneous use with other anticalcineurinic drugs allows the use of reduced doses. Thrombocytopenia and hyperlipidemia are the best known side-effects of sirolimus administration. Alterations in hepatic biochemistry results are also common. Some instances of interstitial pneumonitis associated to its use have been recently reported. In this paper we present a clinical case related to this rare but already confirmed adverse side-effect, which apart from the other more common nosologies occurring in immunosuppressed patients, should be taken into account in the differential diagnosis of interstitial pneumonitis in patients who are being administered this drug.

Topics: Aged; Antilymphocyte Serum; Azathioprine; Cyclosporine; Diagnosis, Differential; Diuretics; Doxazosin; Drug Therapy, Combination; Famotidine; Furosemide; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Male; Muscular Diseases; Mycophenolic Acid; Pneumonia, Bacterial; Postoperative Complications; Prednisone; Sirolimus

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Sirolimus

Interstitial pneumonitis is a temporary side effect of sirolimus therapy and has been described mainly in renal transplant recipients. It is considered to be dose dependent and has been documented in patients receiving at least 5 mg daily, or in patients with blood concentration plateaus > 15 ng/ml. In general, clinical and radiologic features improve after discontinuation and, to the best of our knowledge, no reports of fatalities have been published. Our report documents the death in a heart transplant recipient (52-year-old man) that resulted from a loading-dose administration (15 mg), and we report the association of persistently increased blood concentrations (>20 ng/ml) during most of the scheduled administration period.

Topics: Dose-Response Relationship, Drug; Fatal Outcome; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus

Topics: Diagnosis, Differential; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Middle Aged; Sirolimus

Rapamycin/sirolimus (SR), trade named Rapammune (Wyeth-Ayerst, Sydney, Australia), is a potent immunosuppressive drug associated with myelosuppression, hypertension, hyperlipidemia, and infection. Rapamycin/sirolimus-induced pneumonitis has been described previously in renal transplant recipients, and this report describes a stable heart-lung transplant recipient who developed a pulmonary infiltrate that reversed after ceasing SR therapy. We believe that immunosuppression-induced pneumonitis in a lung allograft is a serious dilemma for lung transplant physicians

Topics: Adult; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Lung Diseases, Interstitial; Lung Transplantation; Male; Sirolimus

Topics: Child; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Lung Diseases, Interstitial; Sirolimus; Tomography, X-Ray Computed

Sirolimus is a recently licensed immunosuppressant for organ transplantation that has been used as basic, adjuvant, or maintenance therapy for prevention of organ rejection. Well-known side effects of this agent are hyperlipidemia and bone marrow suppression. Interstitial pneumonitis is a relatively newly described adverse effect of the drug. A 43-year-old female recipient of a cadaveric kidney developed cough with blood-tinged sputum while receiving sirolimus immunosuppressive therapy. High-resolution computed tomographic scan and chest radiograph revealed interstitial infiltrations over bilateral lower lungs. No evidence of bacterial, fungal, mycobacterial, or viral infection was found and all tests for collagen vascular diseases were negative. Discontinuation of sirolimus resulted in a significant improvement of the lung disease.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Sirolimus

Topics: Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Lung Diseases, Interstitial; Middle Aged; Postoperative Complications; Sirolimus

Topics: Hemorrhage; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Sirolimus

Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia.. Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis.. Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months.. Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

Topics: Aged; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Lymphocytes; Male; Middle Aged; Sirolimus

Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Postoperative Care; Sirolimus

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Sirolimus

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Sirolimus