Lipoproteinaceous Material Research Articles

The influence of genetics on therapeutic developments in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is characterized by the massive accumulation of lipoproteinaceous material within alveoli, which results in progressive respiratory failure. The abnormalities in surfactant clearance are caused by defective pulmonary macrophages, whose terminal differentiation is GM-CSF-dependent. In hereditary PAP, the rupture of GM-CSF signaling is because of mutations in the GM-CSF receptor genes. This review focus on the innovative technologies of gene-correction proposed for the development of new therapeutic strategies, for hereditary PAP patients. Hematopoietic stem cell gene therapy has been successfully experimented in murine models to restore the expression of the GM-CSF receptor, however, a therapeutic approach based on bone marrow transplantation requires a preconditioning, which could be hazardous in PAP patients, who are highly susceptible to pulmonary infections. Gene-corrected pulmonary macrophages, administered directly to the lung, could represent an improved approach. Finally, patient-derived induced pluripotent stem cells seem to be promising to overcome the limited availability of primary patient cells and to generate gene-corrected macrophages, able to recover pulmonary surfactant clearance. WLL is the gold standard therapy for PAP. However, its use in hereditary PAP is limited by the difficulty of performing this technique in paediatric patients and by its purely symptomatic efficacy. The recent advances in genome engineering could provide efficacious strategies for clinical application.

Proteinosis alveolar pulmonar

Pulmonary Alveolar Proteinosis (PAP) is a rare disease characterized by the accumulation of surfactant derived lipoproteinaceous material filling the alveoli, secondary to failure of its clearance by macrophages. Most of the patients are adults that have auto antibodies directed to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). The evolution is towards disturbed gaseous exchange with a wide spectrum of disease from spontaneous recovery to death. There are three forms of PAP: genetic, secondary and autoimmune. Symptoms are scarce and patients may present with dyspnea, dry cough and hypoxemia. Chest X ray shows bilateral opacities and thorax CT depicts ground glass opacities surrounded by septal widening, the so called “crazy paving” pattern. Diagnosis is made on clinical and radiological grounds and confirmed by PAS positive staining of bronchoalveolar lavage material or surgical lung biopsy. Accepted treatmentis whole lung lavage (WLL) with saline. Alternatives are subcutaneous or inhaled GM-CSF, Plasmapheresis or Rituximab, and even modification of the method of WLL and combination of different manner of treatment.

Atypical alveolar proteinosis.

Alveolar proteinosis is a rare pulmonary disease characterized by intra-alveolar accumulation of surfactant composed of lipoproteinaceous material, related to a lack of surfactant resorption by alveolar macrophages. Crazy paving pattern is characteristic, but not specific. The multinodular forms of this affection remain exceptional.

Pulmonary Alveolar Proteinosis- A Case Report

ABSTRACT Background: Pulmonary Alveolar Proteinosis (PAP) is a rare pulmonary disorder caused by a congregation of excessive lipoproteinaceous material in the alveolar spaces due to impaired surfactant metabolism. The congregation of the protein in the alveolar space leads to difficulty in breathing, impaired pulmonary immunity, and susceptibility to both opportunistic and acquired pulmonary infections. Although Pulmonary Alveolar Proteinosis is rare, there are potential treatments. Whole-lung lavage is the most widely accepted therapy and course of treatment. An additional form of therapy, GM-CSF stimulating therapy, uses recombinant deoxyribonucleic acid (DNA) technology to increase white cell production. Purpose: The purpose of this case report is to follow a patient through whole-lung lavage therapy to determine outcome and clinical improvement. Case Description: This case report follows a 55-year-old female patient diagnosed with secondary, idiopathic Pulmonary Alveolar Proteinosis through eight normal saline whole-lung lavages. The patient’s treatment was led by a pulmonologist with previous Pulmonary Alveolar Proteinosis experience. Outcome: By the end of the first four lavages, the patient showed clinical improvement, but during a two-month break from therapy, symptoms returned. Following the break, the patient underwent four additional lung lavage sessions and experienced similar relief as in previous courses of treatment. Discussion: The patient did complete an additional eight lavages to wash out excess lipoproteinaceous material to provide a longer period of symptom relief. The additional form of therapy, GM-CSF, is not a therapy option for this patient as the disease was idiopathic in nature. The last available treatment option for this patient is a lung transplant.

Congenital Pulmonary Alveolar Proteinosis: From Birth to Ten-years of Age.

Pulmonary alveolar proteinosis is a rare lung disease in which lipoproteinaceous material accumulates within the alveoli, interfering with gas exchange. The disease is classified into congenital, secondary, and acquired. The congenital form includes inborn errors of surfactant metabolism, lysinuric protein intolerance and mutations in the components of granulocyte-macrophage colony-stimulating factor receptor. The main symptoms are non-specific. The radiologic appearance of pulmonary alveolar proteinosis is bilateral, symmetric and perihilar airspace consolidation. Bronchoalveolar lavage is crucial for diagnosis of the disease. There is only one ten-year-old patient with diagnosed congenital form in Croatia. What makes him different from other children in the world is that since the ninth month of his life he has been mechanically ventilated. Diagnosis of postnatal alveolar proteinosis should be considered in every infant with respiratory distress with diffuse alveolar and interstitial infiltrate.

Pulmonary alveolar proteinosis and first successful whole lung lavage in Sri Lanka: a case report

BackgroundPulmonary alveolar proteinosis is a rare disease characterized by accumulation of lipoproteinaceous material within alveoli. There are three clinically distinct forms: congenital, acquired and secondary. Whole lung lavage is currently the gold standard therapy for severe cases of pulmonary alveolar proteinosis. In Sri Lanka this is the first reported successful whole lung lavage for a patient with pulmonary alveolar proteinosis.Case presentationWe describe the case of a 15-year-old Sri Lankan girl who presented with symptoms of progressive shortness of breath and dry cough for 6 months’ duration. She had a history of exposure to silica in her household environment. High-resolution computed tomography revealed crazy paving appearance in both lungs suggestive of pulmonary alveolar proteinosis. An open lung biopsy revealed intra-alveolar granular amphophilic material which was strongly periodic acid–Schiff positive and diastase resistant, which is consistent with pulmonary alveolar proteinosis. She was followed up for 2 years with periodical segmental bronchoalveolar lavages which showed minimal improvement in her symptoms as well as in exercise desaturation. Due to severe dyspnea and hypoxemia on exertion, she underwent whole lung lavage. It resulted in a marked improvement in her symptoms, exercise desaturation, and chest X-ray results.ConclusionWhole lung lavage was successfully performed for the first time in Sri Lanka for a patient with pulmonary alveolar proteinosis.

Successful treatment of pulmonary alveolar proteinosis with whole lung lavage and subcutaneous GM-CSF

Abstract Introduction Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of a periodic acid-Shiff-positive lipoproteinaceous material (surfactant) in the distal airways. The standard treatment is whole lung lavage (WLL), however, not all patients respond well to WLL. Aim We present an exciting case report on the successful treatment of the rare disease PAP with WLL and subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF) therapy for 12 weeks. Case study A 20 year-old woman with a 7-month history of progressive shortness of breath was referred to us. Computed tomography of the chest revealed typical geographic ground-glass opacity combined with interlobular septal thickening (crazy paving). Pulmonary function tests showed restriction with severe impairment of diffusion capacity (DLCO 20%). Milky bronchoalveolar lavage fluid (BALF) was detected during bronchoscopy. The cytology of the BALF was consistent with PAP. WLL was performed and subcutaneous GM-CSF was started immediately and continued for 12 weeks. At the end of treatment, the patient's lung function was clearly improved (DLCO 62%). Results and discussion One year after the withdrawal of treatment, the patient remains in good health, with no recurrence of hypoxemia and respiratory symptoms. Different treatment modalities have been applied since PAP was first defined, and WLL has been the preferred first line of treatment. Although our patient‘s condition improved after WLL, her respiratory insufficiency persisted. Consequently, we initiated treatment with subcutaneous GM-CSF. Conclusions WLL significantly improved our patient's condition, and GM-CSF was effective at prolonging pulmonary washout from excess surfactant.

JOURNAL OF PEDIATRIC CRITICAL CARE

Pulmonary alveolar Proteinosis (PAP) is a rare disease whereby the alveolar sacs are filled with a lipoproteinaceous material. The accumulation of this material hinders gas exchange, resulting in a variety of presentations involving all age groups. Symptoms range in severity from mild cough and dyspnea in most patients, to respiratory distress and failure to thrive in infants and young children. Depending on the etiology, PAP cases are classified as being hereditary, secondary, or autoimmune. Despite the different mechanisms underlying these, a unifying pathophysiological concept for PAP exists. Diagnosis is often difficult, and takes time to establish, given the vague nature ofthe presenting symptoms ofthis disease. High resolution computed tomography (HRCT) remains the preferred radiological diagnostic tool. Diagnosis is confirmed by lung biopsy and bronchoalveolar fluid lavage. Management encompasses whole lung lavage (WLL), exogenous GM-CSF therapy, supportive respiratory measures where necessary, and even lung transplant in some severe cases. Children affected with PAP remain a population with high mortality. Pediatric literature is scarce in comparison to PAP described in adults. This paper focuses on reviewing the pathophysiology in context to recent advances in molecular genetics, diagnosis, and management in children with this disease.

Lung Transplant Recipient with Pulmonary Alveolar Proteinosis.

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.

Pulmonary alveolar proteinosis: Experience from a tertiary care center and systematic review of Indian literature.

Background:Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by deposition of lipoproteinaceous material within alveoli, with a variable clinical course. Here, we report an experience of management of PAP at our center. A systematic review of previously reported cases from India is also included in the article.Materials and Methods:This study included patients with primary PAP managed at our center from 2009 to 2015. Diagnosis of primary PAP was based on histopathologic diagnosis on bronchoalveolar lavage or transbronchial lung biopsy and absence of causes of secondary PAP. For systematic review of Indian publications, the literature search was performed using PubMed and EMBASE databases using the terms “pulmonary alveolar proteinosis'” or “alveolar proteinosis” and “India” or “Indian.”Results:During the above-specified period, five patients with diagnosis of PAP were admitted at our center. Median age of patients was 32 years (interquartile range [IQR] 30.5–59); 80% were female. Mean duration (± standard deviation) of symptoms was 6.2 (±1.79) months. Anti-granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies were elevated in 4 out of 5 patients (80%). For management, whole lung lavage (WLL) was done for four patients with median volume of 32.5 (IQR 18–74) L per patient. All the patients showed significant symptomatic as well as improvement in physiological parameters. Subcutaneous GM-CSF and ambroxol were given to 3 patients and 1 patient, respectively. The median follow-up of all patients was 18 (IQR 5–44) months. A systematic review of all Indian studies of PAP revealed thirty publications.Conclusions:WLL is the most common, effective, and safe therapy in patients with PAP. GM-CSF administration is an efficacious treatment for patients with incomplete response after WLL.

Anaesthetic Management of a case of alveolar proteinosis

Pulmonary alveolar proteinosis is a rare type of interstitial lung disease characterised by diffuse involvement and filling of distal air spaces by the amorphous, periodic-acid-schiff positive lipoproteinaceous material. Whole lung lavage is presently the standard mode of management of such cases. A 33-year-old male presented to our centre with cough and breathlessness on exertion. On evaluation he was found to have PAP. He underwent whole lung lavage (WLL) under general anaesthesia using one lung ventilation. We describe the anaesthetic consideration and the challenges faced in such a procedure.

Treatment of Adult Primary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of surfactant-like lipoproteinaceous material in the distal air spaces and terminal bronchi, which may lead to impaired gas exchange. This accumulation of surfactant is due to decreased clearance by the alveolar macrophages. Its primary but most common form is currently considered an autoimmune disease. Better knowledge of the causes of PAP has led to the emergence of alternatives to whole lung lavage, although this is still considered the treatment of choice. Most studies are case series, often with limited patient numbers, so the level of evidence is low. Since the severity of presentation and clinical course are variable, not all patients will require treatment. Due to the low level of evidence, some objective criteria based on expert opinion have been arbitrarily proposed in an attempt to define in which patients it is best to initiate treatment.

Tratamiento de la proteinosis alveolar primaria del adulto

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of surfactant-like lipoproteinaceous material in the distal air spaces and terminal bronchi, which may lead to impaired gas exchange. This accumulation of surfactant is due to decreased clearance by the alveolar macrophages. Its primary, most common form, is currently considered an autoimmune disease. Better knowledge of the causes of PAP have led to the emergence of alternatives to whole lung lavage, although this is still considered the treatment of choice. Most studies are case series, often with limited patient numbers, so the level of evidence is low. Since the severity of presentation and clinical course are variable, not all patients will require treatment. Due to the low level of evidence, some objective criteria based on expert opinion have been arbitrarily proposed in an attempt to define in which patients it is best to initiate treatment.

A 3-Step Therapeutic Strategy for Severe Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of lipoproteinaceous material in the terminal airways. Whole lung lavage (WLL) remains the gold standard treatment but may be particularly challenging incases of severe hypoxemia. We present a 3-step strategy that was used in a patient with PAP-associated refractory hypoxemia and that combined venovenous extracorporeal membrane oxygenation (vvECMO), double-lumen orotracheal intubation, and bilateral multisegmental sequential lavage (MSL). The procedure was well tolerated and permitted weaning from the ventilator.

Rosenthal fibers as a diagnostic marker craniopharyngioma, an intraoperative study

Craniopharyngioma is a sellar tumor with cystic and solid structures. The cystic areas contain aproteinaceous material described as “oil machinery”, little is known about the characteristics of this fluid. We studied a woman 60 years old with a long history of 10 years with visual disturbance until amaurosis. The MRI showed a sellar lesion. Intraoperative findings showed a necrotic yelloswish material with purulent appearance that was diagnosed as abscess. The intraoperative study with crush smears showed a dirty background with necrosis and lipo-proteinaceous material. Few inflammatory cells and abundant Rosenthal fibers formation were also observed. Epithelial cells were lacking. The presence of Rosenthal fibers and lipo-proteinaceous material has been observed in the boundary of this tumor, but those findings have been described as the same and may be helpful for the craniopharyngioma diagnosis. The presence of these indicates rupture of the cystic structure and conditions the output of the material that is damaging normal brain structures.

Anesthetic techniques to facilitate lung lavage for pulmonary alveolar proteinosis in children-new airway techniques and a review of the literature.

Pediatric patients with pulmonary alveolar proteinosis require whole lung lavage to clear the accumulation of lipoproteinaceous material within the alveoli, to maintain respiratory function. Anesthesia for this presents a challenge due to preexisting respiratory failure, and the small diameter and length of the pediatric airway, which is often unable to accommodate existing one-lung isolation and ventilation equipment. Novel techniques to facilitate lung lavage on seven occasions are described and placed in the context of the existing literature to date.

Respiratory strategies and airway management in patients with pulmonary alveolar proteinosis: a review.

Background. Pulmonary alveolar proteinosis is a rare disorder characterized by a large accumulation of lipoproteinaceous material within the alveoli. This causes respiratory failure due to a restriction of gas exchange and changes in the ventilation/perfusion ratio. Treatment methods include noninvasive pharmacological approaches and invasive procedures, such as whole-lung lavage under general anesthesia. Methods. Based on the literature search using free-term key words, we have analyzed published articles concerning the perioperative management of adult and pediatric patients with pulmonary alveolar proteinosis. Results and Discussion. In total, 184 publications were analyzed. Only a few manuscripts were related to anesthetic, respiratory, and airway management in patients suffering from pulmonary alveolar proteinosis. Airway should be strictly separated using a double-lumen tube. Respiratory strategies involve the use of manual clapping, continuous positive airway pressure, high-frequency jet ventilation of the affected lung, and employment of venovenous extracorporeal membrane oxygenation in the most serious of cases. Conclusion. The goal of this review is to summarize the current published information about an anesthetic management strategy with a focus on airway management, ventilation, and oxygenation techniques in PAP patients.

Serum markers in patients with idiopathic pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by PAS positive lipoproteinaceous material accumulation in the pulmonary alveoli, of which autoimmune (APAP) or idiopathic type (IPAP) accounts for about 90%. Several serum markers were reported to be valuable in IPAP diagnosis. However, data in Chinese patients was not available. Here we analyzed the diagnostic value of serum markers in Chinese IPAP patients. Thirty-one IPAP patients, 25 healthy volunteers and 15 patients with other lung diseases were enrolled in the study. Anti-GM-CSF antibody, SP-A, SP-D and YKL-40 levels of the serum samples were tested by ELISA method. LDH, CEA, arterial blood gas analysis and pulmonary function test results were collected and analyzed. Then the difference between the groups and the relationship between the 2 of the markers were tested. The level of serum anti-GM-CSF antibody, SP-A and SP-D [29.80(13.02-53.86) mg/L, (47 ± 30) and (77 ± 57) µg/L respectively] were higher in IPAP patients than in healthy volunteers and disease control patients (P < 0.05). IPAP and disease control groups had higher YKL-40 and LDH levels than the healthy control group (P < 0.05), but no statistical difference between the former 2 groups (P > 0.05). The CEA level of IPAP patients was higher than that of the disease control group (P < 0.05). The sensitivity and specificity of anti-GM-CSF antibody in IPAP diagnosis were both 100% at the cut-off value of 2.46 µg/mL. The LDH, CEA and SP-A levels correlated positively with P(A-a) O₂ and negatively with TL(CO)%, PaO₂ and SaO₂ (P < 0.05). The SP-D level correlated negatively with SaO₂ (P < 0.05), and positively with LDH and CEA level (P < 0.05), so did SP-A (P < 0.05). YKL-40 correlated positively with SP-A but not with other markers. Anti-GM-CSF antibody did not correlate with any of the markers. Serum anti-GM-CSF antibody testing showed high sensitivity and specificity for the diagnosis of APAP, though it did not correlate with disease severity. Serum LDH, CEA, SP-A and SP-D levels were elevated in IPAP patients and correlated well with disease severity. YKL-40 level was also higher in IPAP patients, but it could not be used as a disease severity marker.

English

Paraquat poisoning is characterized by multi-organ failure and pulmonary fibrosis with respiratory failure, resulting in high mortality and morbidity. To serious paraquat patients, the effectiveness of conventional treatments is unsuccessful. Whole lung lavage is a technique that was developed in the 1960s with the purpose of removing lipoproteinaceous material that accumulates in the bronchi of patients with alveolar proteinosis, leading to clinical and functional improvement. Pneumoconioses are characterized as irreversible, progressive respiratory diseases. No effective therapy exists to prevent progression of these diseases. Whole lung lavage might limit the rate of disease progression through the removal of dust, inflammatory cells, and cytokines. Whole lung lavage is also used successfully to treat other lung diseases such as endogenous lipoid pneumonia and mineral oil lipoid pneumonia. Paraquat poisoning could not be controlled by only one method and combined therapies are needed. So, we hypothesized that whole lung lavage will provide a new therapy of acute lung injury caused by paraquat. On the base of conventional therapy for paraquat poisoning, whole lung lavage could be considered in the early time of poisoning and then followed by glucocorticoid for patients with moderate to severe paraquat poisoning. Key words: Paraquat, poisoning, acute lung injury, whole lung lavage.

Primary pulmonary alveolar proteinosis: computed tomography features at diagnosis

Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal accumulation of periodic acid-schiff-positive lipoproteinaceous material in the alveoli. Early diagnosis allows setting up of therapeutic lung lavages, which reduces the need for oxygen supplementation and weight gain. To provide a description of radiological features by CT at the onset of primary PAP in children. The clinical and radiological data of 24 patients, including 16 boys and 8 girls (median age: 12months), diagnosed with a primary form of PAP between April 1992 and May 2012 in a tertiary referral hospital, were retrospectively reviewed. CT images were examined for the presence of alveolar and interstitial elementary lesions. Correlation between clinical and radiological findings was assessed. The types of elementary lesions detected were: ground-glass opacities (n = 24), intralobular lines (n = 24), thickened interlobular septa (n = 22), thickened fissures (n = 21), airspace consolidation (n = 16), hyperinflation (n = 16), cystic lesions (n = 2) and micronodules (n = 1). A crazy-paving pattern was found in 92% of cases. Consolidation and hyperinflation were especially detected in younger children (median age, 8 months, P < 0.01). A density dependent gradient was found. The distribution of the lesions was symmetrical. There was no correlation between radiological and clinical data of severity of the disease. CT findings are suggestive of diagnosis of PAP in immunocompetent children with chronic respiratory failure.