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Chest X-ray, August 2007-there are reticulonodular infiltrates in mid-to-lower lung zone distribution in both lungs. The pulmonary vasculature is grossly normal.
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Pulmonary alveolar proteinosis (PAP) has been associated with the immunosuppressant sirolimus in transplant patients. PAP is a progressive lung disease characterized by the accumulation of surfactant-like material in the lungs leading to decreased pulmonary function with shortness of breath and cough as common symptoms. We report a rare case of sir...
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Respir Case Rep. 2016; 5(3): 161-164 | DOI: 10.5505/respircase.2016.36854
Pulmonary Alveolar Proteinosis and Tracheal Stenosis After Exposure to Fire and Fire Extinghuisher
Mustafa Çörtük1, Elif Tanrıverdi O2, Kenan Abbaslı2, Mehmet Akif Özgül2, Erdoğan Çetinkaya2
1Department of Chest Diseases, Karabük University Faculty of Medicine. Karabük, Tur...
Pulmonary alveolar proteinosis is a rare condition characterized by accumulation of intra-alveolar surfactant. Here, we report a case of interstitial lung disease which developed over the years in a patient with pulmonary alveolar proteinosis.
Citations
... PAP is often difficult to diagnose because its clinical presentation tends to be non-specific with dyspnea being the most common presentation [5]. Because PAP is difficult to diagnose clinically, four out of the five cases of mTOR-inhibitor induced PAP reported in the literature were ultimately diagnosed via lung biopsy; in the other case, biopsy was performed but the results were inconclusive [6][7][8][9][10]. While the gold standard for diagnosis of PAP used to be a lung biopsy, this is no longer routinely recommended because of the invasive nature of the procedure. ...
... In most cases, patients achieve complete or near complete resolution of the disease with the time to resolution ranging from 3 to 12 months. Four out of the five reported cases of mTOR inhibitor-induced secondary PAP resolved without any other clinical intervention; the last one underwent whole lung lavage (WLL) and GM-CSF therapy [6][7][8][9][10]17]. WLL remains the main therapeutic option for PAP and can be a temporizing measure for secondary PAP while addressing the underlying cause [18]. ...
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome that is characterized by the accumulation of excess surfactant in the alveolar space, leading to impaired gas exchange. Sirolimus-induced PAP is an extremely rare entity that has only been described in the literature in a small number of case reports. We present a case of a 39-year-old female with acute lymphocytic leukemia who underwent stem cell transplant, complicated by graft-versus-host-disease (GVHD) involving the skin for which she was treated with steroids, photopheresis, sirolimus, and ruxolitinib. She was admitted to the intensive care unit (ICU) for acute on chronic hypoxic respiratory failure requiring intermittent mechanical ventilation. Computed tomography (CT) of the chest showed thickened inter- and intralobular septa with ground glass opacities and consolidation with a limited geographic pattern. Bronchoalveolar lavage fluid was stained with Periodic acid-Schiff (PAS), which was positive for extracellular proteinaceous material. Autoimmune studies including antibody levels for primary autoimmune pulmonary alveolar proteinosis (PAP) were negative. The patient was diagnosed with sirolimus-induced secondary PAP, and sirolimus was discontinued. A year later, she no longer required supplemental oxygen, and repeat CT imaging showed only faint residual disease. This is the only documented case of sirolimus-induced PAP in a stem cell transplant recipient and the first case reported in which the patient developed severe hypoxic respiratory failure requiring mechanical ventilation. In the right clinical context, PAP can be diagnosed with characteristic high resolution computed tomography (HRCT) findings, serum GM-CSF antibody levels, and bronchoscopy with bronchoalveolar lavage.
... In these cases, the immune cell intrinsic deficiencies might explain the pathophysiology as also in this case monocytes as a pool for AM replenishment in acute lung stress responses might be inadequate or unavailable. However, also other conditions that lead to immunosuppression can cause secondary PAP, like the acquired immunodeficiency syndrome (AIDS) that results from HIV infection [34] or drug-induced immunosuppression for example by corticosteroids [35], busulfan [36], mycophenolate mofetil [37], and leflunamide [38] during treatment of autoimmune diseases or after solid organ transplantation (described, for example, for lung and kidney transplantation) [39,40] as well as hematopoietic stem cell transplantation (HSCT) [41,42]. Besides immunosuppression, chronic inflammation or infections can also be linked to secondary PAP, as described for infections with Cytomegalovirus, Mycobacterium (M.) tuberculosis, Nocardia, or Pneumocystis carinii [43][44][45][46]. ...
Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macrophage populations: interstitial and alveolar macrophages, which occupy different niches and functions. In this review, we provide the latest insights into the multiple roles of alveolar macrophages while unraveling the distinct factors which can influence the ontogeny and function of these cells. Furthermore, we will highlight pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on congenital diseases as well as pulmonary infections and impairment of immunological pathways. Moreover, we will provide an overview about different treatment approaches targeting macrophage dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend our understanding to other macrophage-related disorders.
... There is, however, a single reported case of not PAP but sirolimus-induced granulomatous interstitial pneumonitis. [26 ] Replacement of Sirolimus with other immunosuppresors achieved resolution of pulmonary clinical symptoms and radiological findings in most published cases. PAP is an uncommon adverse reaction of mTOR inhibitors. ...
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of surfactant-like lipoprotein material within distal bronchioles and alveoli due to impaired clearance. Clinically, PAP presents with dyspnea and cough. A 58-year-old Hispanic man presented with 6 months of productive cough, weight loss, and progressively worsening dyspnea. He reported a long history of poorly controlled type 2 diabetes that led to diabetic nephropathy. The patient had a strong passive smoking history for over 30 years and exposure to woodsmoke. He had pulmonary tuberculosis in 2007 and 2012. In 2011, he was diagnosed with renal failure, was dialyzed for a year, and received a renal transplant in 2012. His posttransplant medication regimens included tacrolimus, mycophenolic acid, and prednisone. Six months after the transplant, he suffered graft rejection, managed with steroids and switching from tacrolimus to sirolimus. His physical examination demonstrated scattered inspiratory crackles, and a chest X-ray showed bilateral perihilar ground-glass opacities. PAP was diagnosed through lung biopsy, which showed eosinophilic granular infiltrate withing the alveoli. Sirolimus was switched back to tacrolimus 2 mg in September 2018. PAP diagnosis included hematoxylin and eosin and PAS. Clinical follow-up included oxygen saturation with pulse oximeter and chest X-rays. A 2-month follow-up showed only partial improvement in both symptoms and radiological findings. In January 2019, a follow-up showed complete radiological and symptomatologic resolution. After 5 months, the patient remains asymptomatic with adequate exertion tolerance. PAP remains a diagnosis of exclusion in patients undergoing immunomodulatory therapy with sirolimus and pulmonary symptoms. Reversal can be achieved by switching agents.
... To avoid graft rejection after lung transplantations, patients are given high doses of immunosuppressant and anti-inflammatory drugs [75] such as cyclosporine which has been shown to impair GM-CSF secretion by T lymphocytes [76]. Considering the ability of these treatments to disrupt GM-CSF signalling and myeloid cells production it is not surprising that PAP has been reported in several occasion after lung [77][78][79][80], kidney [81] or unrelated cord blood haematopoietic stem cell [82] transplantation for conditions other than PAP. Unsurprisingly several cases of PAP recurrence after lung transplantation have been documented [11,83]. ...
Pulmonary alveolar proteinosis is a rare disease first described in 1958 by Samuel H Rosen and characterised by the accumulation in the alveolar space of lipoproteinaceous materials due to insufficient catabolism of surfactant lipoproteins by alveolar macro-phages. As a result, gas exchanges between the alveolar space and the blood are impaired, and affected patients develop progressive dyspnoea and pulmonary infections. In the mid-1990s the observation of a pulmonary alveolar proteinosis-like disease in GM-CSF deficient mice led to the discovery of GM-CSF signalling impairments in patients with pulmonary alveolar proteinosis. Additional studies showed that GM-CSF signalling disruption was responsible for incomplete maturation of alveolar macrophages both in mouse and human. Two main types of GM-CSF signalling disruption were observed, autoimmune pulmonary alveolar proteinosis, due to the presence in the blood and bronchoalveolar lavage fluid of neutralising anti-GM-CSF autoantibodies, and hereditary pulmonary alveolar proteinosis due to genetic mutations affecting the expression or the functionality of the GM-CSF receptor. A third type of the disease named secondary pulmonary alveolar proteinosis has also been described in patients suffering from hematologic malignancies, primary immunodeficiency or exposed to various toxic dust. Since its description in 1963 by Dr Jose Ramirez-Rivera, whole lung lavage has been a central therapeutic procedure for pulmonary alveolar proteinosis management. In this article, we will review the critical distinctions between the different forms of pulmonary alveolar proteinosis, as well as the efficacy of current, and prospective therapies for autoimmune and hereditary pulmonary alveolar proteinosis.
... The striking lack of involvement of the native lung in recipients of single-lung transplantation may indicate an alveolar macrophage injury linked to a pathogenic process located specifically in the graft; however, this remains to be determined. In addition, the promoting role of immunosuppressive therapy has previously been evoked in cases of symptomatic PAP reported to develop in lung-or kidney-transplant recipients [2][3][4]10], including almost all well-described cases related to mammalian target of rapamycin inhibitor (mTOR inh) use [4,10]. ...
... The striking lack of involvement of the native lung in recipients of single-lung transplantation may indicate an alveolar macrophage injury linked to a pathogenic process located specifically in the graft; however, this remains to be determined. In addition, the promoting role of immunosuppressive therapy has previously been evoked in cases of symptomatic PAP reported to develop in lung-or kidney-transplant recipients [2][3][4]10], including almost all well-described cases related to mammalian target of rapamycin inhibitor (mTOR inh) use [4,10]. ...
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by accumulation of surfactant in alveolar space related to alveolar macrophage dysfunction. PAP occurs in three clinically distinct forms: autoimmune PAP (90% of cases), secondary PAP and genetic PAP [1]. Secondary PAP may be related to immunosuppressive disorders, with few cases associated with solid-organ transplant [1]. Indeed, to our knowledge, only five cases of symptomatic PAP secondary to lung transplantation have been reported [2–4].
Pulmonary alveolar proteinosis may occur after lung transplantation and may be a cause of respiratory deterioration
... In systemic juvenile idiopathic arthritis, Kimura et al. presented five cases of PAP as one of the rare pulmonary complications; however, anti-GM-CSF antibody positivity was not described [15]. Immunosuppressants can cause SPAP; leflunomide, sirolimus, and mycophenolate mofetil have all been reported to cause PAP161718. Tyrosine kinase inhibitor (TKI)-induced APAP in chronic myeloid leukemia was partially reversed by the discontinuation of TKI, and recurred by re-administering another TKI [19]. Seymour et al. [4] evaluated the case of co-existence of juvenile DM and PAP previously mentioned [3] as drug-induced PAP. ...
Interstitial lung disease (ILD) with dermatomyositis often requires intensive immunosuppressive therapy. Here, we report two cases of pulmonary alveolar proteinosis (PAP) in dermatomyositis with ILD. One case was secondary PAP, and the other was autoimmune PAP positive for the anti-granulocyte macrophage-colony stimulating factor antibody. PAP arose during immunosuppressive therapy and symptoms ceased by attenuating immunosuppression. Exacerbation of pulmonary lesions during intensive immunosuppressive therapy may distinguish PAP from worsening ILD and attenuating immunosuppression should be considered.
... To date, 9 reports have described 11 solid organ recipients who developed PAP. Of these, 3 were lung transplant recipients [2,3] and 8 were kidney transplant recipients [4][5][6][7][8][9][10]. Nine of these patients were on immunosuppressive regimens that included mammalian target of rapamycin-(mTOR-) inhibitors (8 were treated with sirolimus [2,[5][6][7]9] and 1 was treated with everolimus [4]), while 2 were on mTOR-inhibitor sparing regimens that included prednisone, a calcineurin inhibitor, and mycophenolate mofetil (MMF) [3,10]. ...
... Of these, 3 were lung transplant recipients [2,3] and 8 were kidney transplant recipients [4][5][6][7][8][9][10]. Nine of these patients were on immunosuppressive regimens that included mammalian target of rapamycin-(mTOR-) inhibitors (8 were treated with sirolimus [2,[5][6][7]9] and 1 was treated with everolimus [4]), while 2 were on mTOR-inhibitor sparing regimens that included prednisone, a calcineurin inhibitor, and mycophenolate mofetil (MMF) [3,10]. Here we report our experience with a lung transplant recipient treated with prednisone, MMF, and tacrolimus who developed PAP that worsened when MMF was replaced with everolimus. ...
... Although the exact mechanism of mTOR-inhibitorassociated PAP is unclear, an association between this drug class and development of PAP likely exists, as our case is the seventh report of this complication in solid organ transplant recipients treated with mTOR-inhibitors. Of the 9 patients described in the literature, 8 were treated with sirolimus [2,[5][6][7]9] and only 1 was treated with everolimus [4]. We speculate that the difference between the two drugs may be related to the more hydrophilic nature of everolimus [4]. ...
Pulmonary alveolar proteinosis (PAP) is a progressive lung disease characterized by accumulated surfactant-like lipoproteinaceous material in the alveoli and distal bronchioles. This accumulation is the result of impaired clearance by alveolar macrophages. PAP has been described in 11 solid organ transplant recipients, 9 of whom were treated with mammalian target of rapamycin inhibitors. We report a case of a lung transplant recipient treated with prednisone, mycophenolate mofetil (MMF), and tacrolimus who ultimately developed PAP, which worsened when MMF was replaced with everolimus.
... Idiopathic PAP represents 90% of cases and is associated with circulating GM-CSFneutralizing antibodies. Secondary forms occur in the setting of hematological malignancies, inhalation of toxic dust, fumes, or gases, immunosuppression due to infections or drugs, such as sirolimus [16,17], and lysinuric protein intolerance, an autosomal recessive disease caused by defective transport of cationic amino acids [18]. These disorders can impair alveolar macrophage function, leading to surfactant accumulation [9]. ...
We present the case of a 43-year-old woman with a diagnosis of pulmonary alveolar proteinosis, on chronic treatment with sargramostim, a recombinant granulocyte-macrophage colony-stimulating factor, who presented with the nephrotic syndrome secondary to biopsy-proven membranous nephropathy. We discuss potential underlying mechanisms, including speculated effects of sargramostim on mesangial cells and the kidney resident macrophages, and review the existing literature on the potential association between these two disorders.
... PAP that occurs as a consequence of immunosuppressive agents also falls into this category. Although cyclosporin-A has been causally linked with PAP [3] and rare cases of alveolar proteinosis have been reported due to sirolimus, [2] a Medline/PubMed search revealed no occurrence of PAP in renal transplant patients that occurred as a consequence of cyclosporine-mycophenolate combination therapy. ...
... The primary PAP (P-PAP) accounts for approximately 90% of all cases and appears to be mediated through a circulating neutralizing antibody (anti granulocyte-macrophage colony-stimulating factor (GM-CSF) immunoglobulin neutralizing immunoglobulin G antibody ). [2] Since GM-CSF normally plays a vital role in the catabolism of surfactant by alveolar macrophages, its functional deficiency allows surfactant to accumulate. ...
... A failure of scavenging mechanisms lies at the heart of both forms. The prognosis of S-PAP can be unpredictable [2] and the outcome is generally regarded as much worse than that of the autoimmune variety, with a median survival time of around 20 months. [5] A bilateral perihilar infiltrate ("butterfly distribution") involving the lower lobes, but sparing the costophrenic angles in the relevant setting pattern is suggestive of PAP, [6] but pulmonary edema or Pneumocystis jirovecii pneumonia can cast a similar pattern on the X-ray (pleural effusions, unlike in cardiogenic pulmonary edema, are absent in PAP). ...
Pulmonary alveolar proteinosis (PAP) is an orphan disease characterized by the accumulation of excess of surfactant within alveoli and bronchioles. The primary form of PAP (P-PAP; also referred to as idiopathic or autoimmune) is the most common form. It is mediated through a circulating neutralizing antibody against granulocyte-macrophage colony-stimulating factor. Secondary PAP (S-PAP) can be induced by a host of inciting agents and is far more liable to progress to terminal respiratory failure. We describe a rare case of S-PAP occurring in a renal transplant recipient due to mycophenolate and cyclosporine combination-therapy, which resolved spontaneously following withdrawal of these drugs.
... Pulmonary hemorrhage has been reported as a sole histological finding [21] but also in combination with others [18]. Other rare pulmonary manifestations include pulmonary alveolar proteinosis [22], desquamative interstitial pneumonitis [23], hypersensitivity pneumonitis [24], necrotizing granulomas and vasculitis [25], diffuse alveolar damage [26] and non-necrotizing granulomas [19]. Since the reported histological manifestations are not specific for sirolimus toxicity, drug discontinuation with or without steroid therapy is the mainstay of treatment in suspected cases and typically leads to resolution of symptoms within 2 to 4 months [18]. ...
... Macrophage dysfunction due to immunosuppression is considered as one among many other causes of secondary PAP. It has been linked to sirolimus toxicity in 2 previously reported cases [22,42]. PAP histology in our series was documented in both sirolimus (1 case) and non-sirolimus (1 case) groups, suggesting that this is a secondary immunosuppression related tissue reaction that is not directly related to sirolimus toxicity. ...
After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications.
A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications.
The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.
Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395.
