Rare Diffuse Lung Disease Research Articles

Pulmonary alveolar proteinosis: presentation, diagnostic challenges, and management.

Pulmonary alveolar proteinosis is a rare diffuse lung disease; diagnosis and treatment of which is often delayed. We present the case study of a 43-year-old male with a six-month history of worsening breathlessness and non-productive cough referred for specialist respiratory input. Rapid investigations, including high-resolution computed tomography (HRCT) and bronchoalveolar lavage, confirmed the diagnosis of pulmonary alveolar proteinosis. Treatment with whole lung lavage significantly improved pulmonary function and quality of life. We discuss the diagnosis and management of this condition and highlight the importance of early recognition and multidisciplinary teamwork in managing pulmonary alveolar proteinosis.

Case Report: The first reported case of pulmonary alveolar proteinosis with myasthenia gravis in a 27-year-old patient

Background: Pulmonary alveolar proteinosis is a very rare diffuse lung disease characterized by the accumulation of amorphous and periodic acid Schiff-positive lipoproteinaceous material in the alveolar spaces due to impaired surfactant clearance by alveolar macrophages. Three main types were identified: Autoimmune, secondary and congenital. Pulmonary alveolar proteinosis has been previously reported to be associated with several systemic auto-immune diseases. Accordingly, we present the first case report of pulmonary alveolar proteinosis associated with myasthenia gravis. Case: A 27-year-old female patient, ex-smoker, developed a dyspnea on exertion in 2020. The chest X-ray detected diffuse symmetric alveolar opacities. Pulmonary infection was ruled out, particularly COVID-19 infection. The chest scan revealed the “crazy paving” pattern. The bronchoalveolar lavage showed a rosy liquid with granular acellular eosinophilic material Periodic acid-Schiff positive. According to the lung biopsy results, she was diagnosed with pulmonary alveolar proteinosis. The granulocyte macrophage colony-stimulating factor autoantibodies were negative. Nine months later, she was diagnosed with bulbar seronegative myasthenia gravis, confirmed with the electroneuromyography with repetitive nerve stimulation showing significant amplitude decrement of the trapezius and spinal muscles. She was treated with pyridostigmine, oral corticosteroids and azathioprine. Given the worsening respiratory condition of the patient, a bilateral whole lung lavage was performed with a partial resolution of symptoms. Thus, this previously unreported association was treated successfully with rituximab, including improvement of dyspnea, diplopia and muscle fatigability at six months of follow-up. Conclusions: This case emphasizes on the possible association of auto-immune disease to PAP, which could worsen the disease course, as the specific treatment does not exist yet. Hence, further studies are needed to establish clear-cut guidelines for PAP management, particularly when associated to auto-immune diseases.

Pulmonary Alveolar Proteinosis Due to Pneumocystis carinii in Type 1 Hyper-IgM Syndrome: A Case Report

Background: Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease. Reports of rare cases of PAP due to Pneumocystis jirovecii (P. jirovecii) exist in infants with immunodeficiency diseases, but no cases have been reported to date in pediatric patients with type 1 hyper-IgM syndrome (HIGM1).Case Presentation: Herein, we present a case of PAP secondary to P. jirovecii on an infant with HIGM1. He was admitted to our unit because of cough and tachypnea. Lung biopsy confirmed the diagnosis of PAP, whereas hexamine-silver staining of the bronchoalveolar lavage fluid identified P. jirovecii infection. No other probable cause of PAP was observed. Whole exome sequencing indicated a novel c.511dupA (p.I171N*30) hemizygous mutation in the CD40 ligand (CD40LG) gene. He was cured with bronchoalveolar lavage and compound sulfamethoxazole tablets.Conclusions: To our knowledge, this is the first reported case of P. jirovecii infection as a reversible cause of PAP in an infant with HIGM1.

Induced sputum deposition improves diagnostic yields of pulmonary alveolar proteinosis: A clinicopathological and methodological study of 17 cases

ABSTRACTPulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by the accumulation of intra-alveolar lipoprotein-like surfactants. Lung core biopsy and bronchoalveolar lavage (BAL) fluid are currently the two major sources of sampling for diagnosis. In the present study, we assessed the value of induced sputum in diagnosing PAP by transmission electron microscopy and examined the PAP 2-year death rate in Asians. Transmission electron microscopy was performed on the samples from 17 patients with PAP, 13 patients with inflammatory lung diseases, and 13 healthy adults. The PAP patients were followed up for 3–156 months, and inflammatory lung diseases patients or healthy adults for 12–36 months. The ultrastructural features including diagnostic lamellar bodies of induced sputum deposition (ISD) samples were similar to that of the BAL fluid sediment. However, the rates of lamellar bodies were 73.7% in the ISD group, significantly higher than the spontaneous sputum deposition (SSD) group (42.1%, P < .0487) and similar to the BAL sediment (76.2%) and the lung biopsy (54.5%) groups. The overall 2-year death rate of our PAP patients was 17.6% (3/17), not statistically different from the healthy adults and patients with inflammatory diseases (0/13, P = .237 for both). ISD may be the preferred non-invasive sampling method for diagnosing PAP by electronic microscopy because of the higher diagnostic yield than SSD. The diagnostic yields of this noninvasive method were similar to that of lung core biopsy and BAL.

Pulmonary alveolar microlithiasis: two case reports and review of the literature

Pulmonary alveolar microlithiasis is a rare diffuse lung disease characterised by deposition of calcium phosphate within the alveolar airspaces. The disease is usually discovered from birth up to 40 yrs of age and is often diagnosed incidentally during radiography of the chest for other reasons. Many patients are asymptomatic and the majority of patients either have normal or restrictive pulmonary function. The clinical course of the disease varies. While it remains static in some patients, it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale in others. With the exception of lung transplantation, there is no known effective treatment for the disease. Although the aetiology remains unclear, mutations of the solute carrier family 34 (sodium phosphate), member 2 gene (the SLC34A2 gene), which encodes a sodium/phosphate co-transporter, are considered to be the cause of the disease. We present two cases of pulmonary alveolar microlithiasis with different mutations in the SLC34A2 gene that have not been previously described, and a review of the literature.

Proteome analysis of bronchoalveolar lavage in pulmonary langerhans cell histiocytosis

BackgroundPulmonary Langerhans-cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by clusters of Langerhans cells, organized in granulomas, in the walls of distal bronchioles. It is a diffuse lung disease related to tobacco smoking but otherwise of unknown etiopathogenesis.MethodsIn this study we used a proteomic approach to analyze BAL protein composition of patients with PLCH and of healthy smoker and non-smoker controls to obtain insights into the pathogenetic mechanisms of the disease, to study the effect of cigarette smoking on susceptibility to PLCH and to identify potential new biomarkers.ResultsTwo-dimensional electrophoresis and image analysis revealed proteins that were differently expressed (quantitatively and qualitatively) in the three groups of subjects. The proteins were identified by mass spectrometry and have various functions (antioxidant, proinflammatory, antiprotease) and origins (plasma, locally produced, etc.). Many, such as protease inhibitors (human serpin B3) and antioxidant proteins (glutathione peroxidase and thioredoxin) are already linked to PLCH pathogenesis, whereas other proteins have never been associated with the disease. Interestingly, numerous proteolytic fragments of plasma proteins (including kininogen-1 N fragments and haptoglobin) were also identified and suggest increased proteolytic activity in this inflammatory lung disease. Differences in protein expression were found between the three groups and confirmed by Principal Component Analysis (PCA).ConclusionAnalysis of BAL proteomes of PLCH patients and of smoker and non-smoker controls also proved to be useful for researching the pathogenetic mechanisms and for identifying biomarkers of this rare diffuse lung disease.

Pulmonary Alveolar Proteinosis: An Overview for Internists and Hospital Physicians

Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by abnormal accumulation of surfactant-associated phospholipoproteinaceous material in the pulmonary alveoli. The clinical findings of slow-onset dyspnea or dyspnea on exertion and persistent dry cough are nonspecific; radiographic findings of “bat-wing configuration” and “crazy paving” appearance in high-resolution computed tomography are suggestive, but not diagnostic of PAP. The current gold standard of PAP diagnosis involves histopathological examination of alveolar specimens obtained from bronchoalveolar lavage and transbronchial lung biopsy. The characteristic histopathological features are intraalveolar periodic acid Schiff (PAS)-positive eosinophilic homogeneous material with well-preserved architecture of alveolar septa. The current standard medical treatment of PAP involves the physical removal of the surfactant-associated phospholipoproteinaceous alveolar deposit by whole lung lavage, which causes clinical and radiological improvement in a majority of patients. Some patients have been successfully treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF).

CD8+ T-cell alveolitis in familial pulmonary alveolar microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare diffuse lung disease characterised by the accumulation of calcium phosphate microliths within the alveoli. The causative mechanism of PAM has only recently been discovered, and involves a gene mutation of sodium phosphate co-transporter, which is expressed by alveolar epithelial cells. This mutation may have variable consequences on the clinical phenotype. However, pulmonary cell immune phenotyping in familial PAM has not previously been assessed. In the present article, the analysis of bronchoalveolar lavage fluid of two siblings with PAM diagnosis revealed a pattern of lymphocytic alveolitis with accumulation of CD8+ T-cells. The clonal complexity of this lymphocyte's population was assayed by spectratyping, which showed an oligoclonal accumulation of T-cells with a restricted variable beta T-cell receptor (TCR) gene usage. TCR analysis in peripheral blood lymphocytes revealed no abnormal patterns of T-lymphocytes. In the pulmonary alveolar microlithiasis familial cases reported, CD8-mediated maladaptive immune response may have taken place in the bronchoalveolar compartment. The relationship between this immune dysregulation and genetic background in pulmonary alveolar microlithiasis warrants further investigation.