Primary Pulmonary Alveolar Proteinosis Research Articles

Pulmonary alveolar proteinosis in Taiwan

Pulmonary alveolar proteinosis (PAP) is rare disease manifested as alveolar macrophage dysfunction and abnormal accumulation of surfactant protein in the alveoli. In this nationwide, population-based study, we investigated the epidemiology of PAP in Taiwan, and discovered the comorbidities and prognostic factors of PAP. From the National Health Insurance Research Database (NHIRD), we obtained comprehensive information about all patients of PAP in Taiwan between 1995 and 2013. The incidence, baseline characteristics comorbidities, and prognostic factors of PAP were investigated. The annual incidence rate of PAP was around 0.79 (range: 0.49-1.17) patients per million people after 2000, and the prevalence rate was 7.96 patients per million people by the end of 2013. In total, 276 patients of PAP were identified, including 177 (64%) and 99 (36%) patients with primary and secondary PAP, respectively. The median age of diagnosis was 53.8 years. The median survival was 9.6 years after the initial PAP diagnosis, and the 5-year survival rate was 65.96%. Twenty (7%) patients received whole lung lavage (WLL) within three months after the diagnosis had significantly better survival compared to the others. Multivariable Cox regression analyses showed that elder age, secondary PAP, and malignancy were associated with poorer survival, while WLL within 3 months of diagnosis might greatly improve the survival. We demonstrated the epidemiology of PAP in Taiwan, showing several poor prognostic factors and the potential effectiveness of WLL. Further prospective studies based on registry are warranted to improve the diagnosis and treatment of PAP.

Pulmonary Alveolar Proteinosis: An Overview and Emerging Therapeutics

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by surfactant accumulation in the alveoli, which results in impaired gas exchange. There are three types of PAP: primary, secondary and congenital. Autoimmune PAP, which is under the category of primary PAP, is the most common form, and is caused by an impairment in granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling, due to the presence of anti-GM-CSF autoantibodies. While some patients with PAP remain asymptomatic, most present with progressive dyspnoea of insidious onset that, rarely, can progress to respiratory failure and death. Currently, there is no known cure and no approved therapies for PAP. Whole-lung lavage remains the gold-standard treatment; however, several novel and promising targeted therapies are being actively investigated.

Whole lung lavage in pulmonary alveolar proteinosis: anesthetic management and challenges

BackgroundPulmonary alveolar proteinosis is a rare disorder characterized by alveolar obstruction secondary to the collection of lipoproteinaceous material in the alveoli leading to a spectrum of respiratory illness ranging from mild to severe respiratory failure. Whole lung lavage considered the gold standard for the treatment of PAP is performed under general anesthesia and presents a unique set of challenges to the anesthesiologist. The procedure involves manually removing the lipoproteinacious material by repeating aliquots of fluids and draining periodically after percussion. When done effectively it is quite effective and life-saving procedure.Case presentationA 39-year-old female presented with history of gradually progressive shortness of breath, diagnosed to have primary pulmonary alveolar proteinosis for which bilateral whole lung lavage was planned. During the lavage cycles, patient had episodes of desaturation to 60% during which the double lung ventilation was resumed. Her serial ABG revealed a deteriorating oxygenation. In view of increased oxygen requirements, the procedure was carried out in two stages. She made a complete recovery after the procedure.ConclusionsA multidisciplinary team working with good communication, use of adequate back up plans, meticulous lung separation with double lumen tube, vigilant intraoperative monitoring, short-term postoperative ventilation go a long way in achieving adequate gas exchange in patients with respiratory failure due to pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis: from classification to therapy.

Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome characterised by the accumulation of surfactant lipoproteins within the alveoli. According to various pathogenetic mechanisms and aetiologies, PAP is classified as primary, secondary or congenital. Primary PAP is led by a granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling disruption; the autoimmune form is driven by the presence of anti GM-CSF autoantibodies and represents 90% of all the PAP cases; and the hereditary form is the result of mutations in genes encoding GM-CSF receptor. Secondary PAP is associated with various diseases causing a reduction in function and/or number of alveolar macrophages. Congenital PAP emerges as a consequence of corrupted surfactant production, due to mutations in surfactant proteins or lipid transporter, or mutations affecting lung development. The clinical manifestations are various, ranging from insidious onset to acute or progressive respiratory failure, including premature death within the first days of life in neonates with congenital surfactant production disorders. The diagnostic workup includes clinical and radiological assessment (respiratory function test, high-resolution chest computed tomography), laboratory tests (anti-GM-CSF autoantibodies dosage, GM-CSF serum level and GM-CSF signalling test), and genetic tests. Whole-lung lavage is the current gold standard of care of PAP; however, the therapeutic approach depends on the pathogenic form and disease severity, including GM-CSF augmentation strategies in autoimmune PAP and other promising new treatments.Educational aimsTo update knowledge about a rare respiratory syndrome, pulmonary alveolar proteinosis, in order to promote early diagnosis and correct management.To highlight recent treatment options based on pathogenesis and disease severity.

Management of primary pulmonary alveolar proteinosis: A multicentric experience.

Background:Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar accumulation of surfactant material with reduced lung function and resulting hypoxemia. It is characterized by a variable clinical course, and whole lung lavage (WLL) is the standard treatment. Herein, we report our multicentric experience of management of primary PAP.Materials and Methods:This retrospective study included patients with PAP managed at various armed forces respiratory centers from 2009 to 2019. The diagnosis of primary PAP was based on histopathologic confirmation on transbronchial lung biopsy or open lung biopsy and absence of causes of secondary PAP. We analyzed the response to WLL in these patients as well as the safety of the procedure.Results:During the above-specified period, ten patients with a diagnosis of PAP were admitted to various armed forces respiratory centers. The median age of the patients was 34.5 years (range 23–59); there were nine males (90%). The mean duration (± standard deviation) of symptoms was 10.8 (±2.70) months. For management, WLL was done for eight patients with a median volume of 23.5 L (range 18–45) per patient. All the patients showed significant symptomatic response as well as improvement in physiological parameters with no major complications. The median follow-up of all patients was 18 (range 5–44) months.Conclusions:WLL is a safe, effective therapy in an experienced setting in patients with PAP and provides long-lasting benefits.

Pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages. PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis. PAP can be classified into different types on the basis of the pathogenetic mechanism: primary PAP is characterized by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling and can be autoimmune (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits); secondary PAP results from various underlying conditions; and congenital PAP is caused by mutations in genes involved in surfactant production. In most patients, pathogenesis is driven by reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance. PAP has a prevalence of at least 7 cases per million individuals in large population studies and affects men, women and children of all ages, ethnicities and geographical locations irrespective of socioeconomic status, although it is more-prevalent in smokers. Autoimmune PAP accounts for >90% of all cases. Management aims at improving symptoms and quality of life; whole-lung lavage effectively removes excessive surfactant. Novel pathogenesis-based therapies are in development, targeting GM-CSF signalling, immune modulation and cholesterol homeostasis.

PULMONARY ALVEOLAR PROTEINOSIS PRESENTING AS INTRACEREBRAL NOCARDIOSIS

SESSION TITLE: Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/09/2018 07:30 am - 08:30 am INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disorder with an incidence of 0.5 / million people [1]. PAP is caused by the accumulation of surfactant in the alveoli, leading to hypoxemic respiratory failure and increased risk of opportunistic infections [2]. First-line therapy after infection eradication is whole-lung lavage. Treatment with exogenous granulocyte macrophage colony stimulating factor (GM-CSF) is under investigation. PAP can be a diagnostic challenge due to its low prevalence and nonspecific presentation. Here we describe a unique presentation that was diagnosed as PAP. CASE PRESENTATION: A 56 year old male farmer, never smoker, with no past medical history presented with right-sided weakness, two months of dyspnea, and dry cough. Brain MRI demonstrated multiple cerebral rim-enhancing abscesses (Fig 1A). He underwent a craniotomy and evacuation of cerebral abscesses with acid fast cultures positive for Nocardia farcinica. Chest CT showed a "crazy paving" pattern consistent with PAP (Fig 1B, C). Serum anti GM-CSF antibody was positive. Bronchoscopy showed opaque fluid on bronchoalveolar lavage, with negative cultures, and clumps of amorphous proteinaceous material consistent with PAP. Disseminated Nocardia was treated with ciprofloxacin for 1 year and sulfamethoxazole/ trimethoprim for 6 months. He underwent a whole lung lavage with resolution of symptoms. DISCUSSION: PAP is caused by surfactant accumulation due to incomplete removal by alveolar macrophages. Autoimmune PAP (primary PAP) accounts for the majority of cases [1]. Autoimmune PAP is caused by anti GM-CSF antibodies that disrupt macrophage activation, antigen presentation, and phagocytosis [2]. Secondary PAP is thought due to a relative deficiency of GM-CSF usually in the setting of hematologic diseases or dust exposures. The ensuing macrophage dysfunction leads to increased infection risk. Opportunistic infections including Nocardia, Mycobacterium, and fungi in otherwise immunocompetent patients with PAP have been previously reported [2]. In a report of 7 patients with disseminated Nocardiosis without PAP, 5 patients were found to have anti GM-CSF antibodies; two of these patients were also found to have radiographic characteristics of PAP [3]. CONCLUSIONS: Primary PAP is a rare autoimmune disorder that confers an immunocompromised state due to impaired alveolar macrophage activation. Opportunistic infections such as Nocardiosis are frequently seen with PAP. Eradication of the opportunistic infections, and targeted whole lung lavage are effective at relieving hypoxia in PAP. A high diagnostic suspicion is essential in the work-up of PAP. Reference #1: Clinics in Chest Medicine. 2016;37(3):431-440. https://doi.org/10.1016/j.ccm.2016.04.006 Reference #2: Journal of Infectio. 2012;65(2):173-179. https://doi.org/10.1016/j.jinf.2012.03.020 Reference #3: Clinical Infectious Disease. 2014;60(7):1017-1025. https://doi.org/10.1093/cid/ciu968 DISCLOSURES: No relevant relationships by David Dennis, source=Web Response No relevant relationships by Ulysses Magalang, source=Web Response No relevant relationships by Virgil Secasanu, source=Web Response

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.

Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis

ObjectivesAlthough the serum granulocyte-macrophage colony stimulating factor autoantibody (GMAb) levels have been recognised as a diagnostic marker in primary pulmonary alveolar proteinosis (PAP), their role in PAP with occupational inhalational...

Serial bronchoscopic lung lavage in pulmonary alveolar proteinosis under local anesthesia.

Pulmonary alveolar proteinosis (PAP) is a rare disease, characterized by alveolar accumulation of surfactant composed of proteins and lipids due to defective surfactant clearance by alveolar macrophages. Mainstay of treatment is whole lung lavage, which requires general anesthesia. Herein, we report a case of primary PAP, successfully treated with serial bronchoscopic lung lavages under local anesthesia.

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.

Primary pulmonary alveolar proteinosis

No abstract available Galle Medical Journal, Vol 18: No. 2, September 2013;Page 31-32 DOI: http://dx.doi.org/10.4038/gmj.v18i2.6200

Primary pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis is an uncommon disease characterized by the accumulation of surfactant proteins and phospholipids within the alveolar spaces. Acquired disease can be idiopathic (primary) and secondary. The prevalence of acquired pulmonary alveolar proteinosis is about 0.37 per 100,000 persons. Common symptoms are dyspnea and cough. Chest X-ray shows bilateral perihilar infiltrates. Open-lung biopsy is the gold standard for the diagnosis. Treatment includes whole-lung lavage, application of granulocyte-macrophage colony-stimulating factor and lung transplantation. We reported a 51 year-old man with primary form of the disease. It was the second case of this extremely rare disease in the past 30 years in our clinic. The symptoms were long-lasting dry cough, fever and physical deterioration. Chest Xray revealed bilateral pulmonary infiltrates; computed tomography showed patchy ground-glass opacification with interlobular thickening. The diagnosis was established by open lung biopsy. Additional tests were performed to exclude secondary form of the disease. We presented a rare clinical entity with typical clinical features and clinical and radiological course of the disease, in order to improve differential diagnostic approach to patients with bilateral lung infiltrations. In patients with pulmonary alveolar proteinosis timely diagnosis and adequate treatment can improve a prognosis.

Lobar Flexible Fiberoptic Lung Lavage: Therapeutic Benefit in Severe Respiratory Failure in Pulmonary Alveolar Proteinosis and Influenza A H1N1 Pneumonia

Lobar fiberoptic lung lavage is a well-known procedure used in primary pulmonary alveolar proteinosis (PAP); the use of this procedure has increased in the recent years. This procedure has also been used in other pulmonary diseases such as desquamative interstitial pneumonia with good results. We describe a case of extremely severe respiratory failure due to concurrence of PAP and Influenza A H1N1 virus pneumonia which resolved with the help of this procedure. The patient, a 41-year-old woman, needed less mechanical ventilation after undergoing lobar fiberoptic bronchoscopic lavage. Moreover, a rapid and progressive improvement in the computed tomography of the lungs was observed. Flexibile fiberoptic bronchoscopic lobar lavage is a simple, safe procedure used not only in milder disease, but also in particular severe cases in which the physiological derangement of whole lung lavage would not be tolerated by patient or when extra-corporeal membrane oxygenation is not available.

Gravidez de termo em doente com proteinose alveolar e insuficiência respiratória grave

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by abnormal accumulation of a lipoproteinaceous material in the alveoli, which may lead to respiratory failure and has an associated high risk for infections. The mainstay treatment for PAP is whole lung lavage. A pregnant woman, previously diagnosed with primary PAP, the most common form of PAP, was admitted with dyspnea and worsening respiratory function. In one month period, a whole-lung bronchopulmonary lavage was performed twice, with clinical and functional improvement. Pregnancy was carried to term and a healthy baby was delivered. The mechanisms of respiratory impairment are discussed as well as treatment options and response.

Hereditary pulmonary alveolar proteinosis caused by recessive CSF2RB mutations

To the Editors: Pulmonary alveolar proteinosis (PAP) is a syndrome characterised by accumulation of surfactant in alveoli resulting in respiratory insufficiency 1. Surfactant homeostasis is critical for lung function and is tightly regulated, in part, by pulmonary granulocyte-macrophage colony-stimulating factor (GM-CSF), which is required for surfactant clearance by alveolar macrophages 2 and alveolar macrophage maturation 1. The effects of GM-CSF are mediated by cell-surface receptors composed of GM-CSF-binding α-chains and affinity-enhancing β-chains (encoded by CSF2RA and CSF2RB , respectively) 3. Ligand binding activates signalling via multiple pathways including the signal transducer and activator of phosphorylation (STAT)5 4. Disruption of GM-CSF signalling causes PAP by impairing surfactant catabolism in alveolar macrophages 1. In 90% of patients, PAP is caused by neutralising GM-CSF auto-antibodies 5, 6. Through the Rare Lung Diseases Network global PAP detection programme, we identified PAP caused by recessive CSF2RA mutations and developed novel diagnostic methods to identify patients with PAP caused by GM-CSF receptor dysfunction 4, 7. Herein, we report a case of hereditary PAP caused by disruption of GM-CSF receptor β-chain function. A previously healthy 9-yr-old female presented with bilateral pneumonia, followed 3 months later by progressive dyspnoea of insidious onset. The diagnosis of PAP was suggested by chest radiograph findings, high-resolution computed tomography and bronchoalveolar cytology, and was confirmed by surgical lung biopsy. Pulmonary histopathology was typical of primary PAP (fig. 1) and she was successfully treated by serial whole lung lavage therapy. Details of the case history are included in the online supplement. A GM-CSF auto-antibody test was negative and the serum GM-CSF level was increased (25.9 pg·mL−1) suggesting GM-CSF receptor dysfunction as the molecular basis of PAP 4, 7. A molecular evaluation was undertaken and included GM-CSF receptor detection, STAT-5 phosphorylation, CSF2RA …

Alveolar proteinosis syndrome: pathogenesis, diagnosis, and management

This review discusses the most recent clinical and basic research literature on pulmonary alveolar proteinosis (PAP) as it relates to pathogenesis, diagnosis, and management. The discovery of Granulocyte macrophage-colony stimulating factor (GM-CSF) and the alveolar macrophage as critical regulators of surfactant protein and lipid homeostasis has led to significant advances in PAP. Adults affected by PAP have circulating neutralizing anti-GM-CSF antibodies. Reduced localized GM-CSF activity in the lung (from neutralizing anti-GM-CSF antibodies), decreases alveolar macrophage surfactant degradation with surfactant excess and accumulation. Cause, source of antibodies or downstream effects of GM-CSF deficiency is speculative. GM-CSF antibodies above a threshold level have proved to be a useful diagnostic test. Research towards therapy has focused on improving the technique for therapeutic whole lung lavage as well as overcoming effects of neutralizing anti-GM-CSF, which include GM-CSF therapy (systemic and inhaled) and anecdotal reports of anti-B cell therapy. Whereas this approach has been somewhat successful for primary PAP, other causes of PAP (i.e. alveolar macrophage dysfunction, surfactant protein alterations) are still without therapy. Understanding of the pathogenesis of PAP has greatly increased in the last decade; study has brought better comprehension of lung biology and recognition of the critical role for GM-CSF and alveolar macrophage in surfactant clearance. Balance between resident immune cell population and normal lung function still needs further study. Resident alveolar macrophages have an essential role in surfactant homeostasis. With this knowledge more effective diagnostic tests (e.g. anti-GM-CSF antibody) and therapies for PAP are under investigation.

Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.

Pulmonary alveolar proteinosis with myeloproliferative syndrome with myelodysplasia: Bronchoalveolar lavage reduces white blood cell count

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by surfactant component accumulation in the alveolar space. Primary PAP is likely an autoimmune disorder caused by antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF). When an underlying disease causes PAP, this is called secondary PAP. Hematologic malignancies are an important cause of secondary PAP. As the pathogenesis of primary PAP has become more fully understood, improvements in diagnostic and therapeutic approaches have followed. However, when PAP is secondary to an underlying hematologic malignancy, much remains unclear. Here we describe for the first time a patient with hybrid myelodysplastic syndrome/myeloproliferative syndrome and PAP who had a marked decrease in her white blood cell count following a transbronchial biopsy accompanied by bronchoalveolar lavage (BAL). Similar significant decreases in WBC count accompanied clinical improvement following two unilateral BALs. Given that patients with pulmonary alveolar proteinosis frequently have elevated GM-CSF in bronchoalveolar fluid, this observation provides a unique vantage point to understand the pathophysiology of secondary PAP.

Primary Pulmonary Alveolar Proteinosis: A Case Report and a Review of the Literature

Primary Pulmonary Alveolar Proteinosis: A Case Report and a Review of the Literature