Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a disease of alveolar accumulation of phospholipoproteinaceous material that results in gas exchange impairment leading to dyspnea and alveolar infiltrates. There are three forms of PAP: congenital, acquired and idiopathic; of which the latter two are predominant in the adult population. Previous case studies have found that the acquired form can be secondary to various autoimmune, infectious, malignant and environmental etiologies. Recent advances in the understanding of the pathophysiology of PAP demonstrate that the idiopathic form is due to antigranulocyte macrophage-colony stimulating factor antibodies. Therapeutic targets that replace granulocyte macrophage colony stimulating factor or remove these antibodies are being actively developed. The current standard of care is to perform whole lung lavage on these patients to clear the alveolar space to help improve respiratory physiology. A case of PAP is reported, followed by a literature review on the diagnosis and management of this rare condition with the aim of increasing awareness among physicians when treating patients who present with alveolar infiltrates.     

Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis is a rare disease characterised by excessive accumulation of surfactant components in the alveoli and the distal airways with minimum inflammatory reaction and fibrosis of pulmonary interstitium. Three clinical forms of pulmonary alveolar proteinosis are distinguished - congenital, primary and secondary. Results of ultrastructural, biochemical and functional analyses and studies performed on genetically modified mice support the presumption that accumulation of surfactant in pulmonary alveolar proteinosis is a result of a degradation disorder and of diminished clearance of the surfactant from the alveolar space rather than of excessive synthesis of surfactant components. Over the last 15 years, significant discoveries have been made which have helped to clarify the etiology and pathogenesis of the disease. A number of gene mutations have been discovered which lead to the development of congenital pulmonary proteinosis. Apart from impaired surfactant protein function, a key role in the development of pulmonary alveolar proteinosis is played by the signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. The role of GM-CSF has been proven especially in primary pulmonary alveolar proteinosis which is currently considered an auto-immune disease involving the development of GM-CSF neutralising autoantibodies. In most cases, the prognosis for the disease in adult patients is good, even though there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is considered to be the standard method of treatment. In recent years, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of pulmonary alveolar proteinosis.     

Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis is a rare syndrome characterized by intra-alveolar accumulation of surfactant components and cellular debris, with minimal interstitial inflammation or fibrosis. The condition has a variable clinical course, from spontaneous resolution to respiratory failure and death due to disease progression or superimposed infections. The standard of care for alveolor proteinosis therapy is represented by whole lung lavage. Important discoveries have been made in the last decade with respect to disease pathogenesis and therapy of both congenital and acquired forms of the disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway has been shown to be involved in the disease pathogenesis of both acquired and congenital disease. Furthermore, anti-GM-CSF blocking autoantibodies have been found in the serum and bronchoalveolar lavage fluid and seem to interfere with the surfactant clearance by alveolar macrophages in many acquired cases. In the congenital form, the most common defects identified to date are several mutations of the genes encoding GM-CSF receptor subunits or surfactant proteins. Using GM-CSF as a therapeutic tool has also been shown to be effective in at least half of the acquired cases treated, while the importance of quantitative determination of anti-GM-CSF antibodies before and during the course of the therapy, as well as the autoantibody titer-GM-CSF dose relationship are to be elucidated. The congenital form of the disease does not respond to therapy with GM-CSF, consistent with the known primary defects and differences in disease pathogenesis.     

Pulmonary alveolar proteinosis

We report a 68-year-old female who presented with chronic cough and progressive dyspnoea. Computed tomography of the thorax and subsequent bronchoscopy confirmed the diagnosis of pulmonary alveolar proteinosis (PAP), which was treated with whole lung lavage. This case is reported in view of the low incidence of PAP.     

Pulmonary alveolar proteinosis

PAP is an ultra‐rare disease in which surfactant components, that impair gas exchange, accumulate in the alveolae. There are three types of PAP. The most frequent form, primary PAP, includes autoimmune PAP which accounts for over 90% of all PAP, defined by the presence of circulating anti‐GM‐CSF antibodies. Secondary PAP is mainly due to haematological disease, infections or inhaling toxic substances, while genetic PAP affects almost exclusively children. PAP is suspected if investigation for ILD reveals a crazy‐paving pattern on chest CT scan, and is confirmed by a milky looking BAL that gives a positive PAS reaction indicating extracellular proteinaceous material. PAP is now rarely confirmed by surgical lung biopsy. WLL is still the first‐line treatment, with an inhaled GM‐CSF as second‐line treatment. Inhalation has been found to be better than subcutaneous injections. Other treatments, such as rituximab or plasmapheresis, seem to be less efficient or ineffective. The main complications of PAP are due to infections by standard pathogens (Streptococcus, Haemophilus and Enterobacteria) or opportunistic pathogens such as mycobacteria, Nocardia, Actinomyces, Aspergillus or Cryptococcus. The clinical course of PAP is unpredictable and spontaneous improvement can occur. The 5‐year actuarial survival rate is 95%.     

Pulmonary alveolar proteinosis: Determination of prostaglandins and leukotrienes in lavage fluid

In bronchoalveolar lavage fluid from a patient with pulmonary alveolar proteinosis, leukotrienes and prostaglandins were measured on 4 occasions during 10 months. Large amounts of leukotriene-C₄-like substances (10–25 nmol) and oxygenated products of leukotriene B₄ were detected. These substances were characterized by the measurement of absorption spectra in high-performance liquid chromatography, biological activities by means of guinea pig lung parenchymal strips, and immunoreactivities in radioimmunoassay. The cyclooxygenase products of arachidonic acid were present in lower amounts (40–500 pmol). Our results indicate that arachidonic acid metabolites are mainly present in the first fraction of the lavage fluid. These substances may have been formed by alveolar macrophages.     

Pulmonary alveolar proteinosis and its treatment with total pulmonary lavage in the Czech Republic

Pulmonary alveolar proteinosis is a rare disease characterized by accumulation of a large amount of both components of surfactant, proteins and phospholipids in alveoli and terminal bronchioles. This cumulation may lead to impaired gas exchange and result in respiratory insufficiency. The disease may develop in neonatal age or later in adult age. Two congenital forms are known. The disease occurs however also in people with neoplastic disease, during cytostatic treatment, during inhalation of inorganic dusts. A dominant symptom is progressing dyspnoea. Asymptomatic forms exist also. The most effective therapeutic method is overall pulmonary lavage. The authors implemented in 1999 the first overall pulmonary lavage in the Czech Republic in the General Faculty Hospital in Prague in a 60-year-old female patient.     

Pulmonary alveolar proteinosis: step-by-step perioperative care of whole lung lavage procedure.

BACKGROUND: Pulmonary alveolar proteinosis is a rare disease characterized by the accumulation of surfactant-like material within the alveolar spaces that causes progressive respiratory failure. Improvement can be achieved with whole lung lavage. OBJECTIVE: Our objective was to conduct a study of the feasibility of treating pulmonary alveolar proteinosis in a community hospital. METHODS: Five patients were treated. We assessed procedure pulmonary functions. RESULTS: No major sequelae occurred. Each lung was lavaged with 12 to 20 L of normal saline in cycles of 970 +/- 150 mL each (mean +/- standard deviation), over 106 +/- 49 minutes. Extubation was performed when compliance of the lavaged lung was restored. All patients showed subjective improvement. Resting and exercise oxygen saturation improved within 1 week after the lavage. A significant improvement was also noted in forced expiratory volume in 1 second, forced vital capacity, and maximal oxygen uptake, whereas total lung capacity and carbon monoxide single-breath diffusion capacity remained unchanged. CONCLUSION: Although retrospective and based on a small sample size, our results suggest that whole lung lavage may be performed safely even in medical centers that have limited experience, if strict adherence to a protocol is maintained.