By Ilaria Campo, Davide Piloni, Francesca Mariani
Pulmonary alveolar proteinosis (PAP) is a diffuse pulmonary disease characterized by the accumulation of surfactant lipids and proteins, in the distal air spaces, which results in impaired gas transfer [1, 2]. Autoimmune PAP accounts for the vast majority of cases in humans and is caused by autoantibodies directed towards granulocyte-macrophage colony-stimulating factor (GM-CSF), which causes a defect in the function of alveolar macrophages linked to the disruption of surfactant homeostasis . Whole lung lavage (WLL) is the current standard of care for PAP patients and although it is effective in the majority of cases by physically removing the accumulated surfactant , disease persistence is not an unusual outcome, sometime also after repeated WLL treatments . Here we will briefly examine three different clinical cases, characterized by different presentation and clinical progression.
Case 1: 56-year-old man, ex-smoker. In May 2012 a histological diagnosis of PAP was done, following the incidental finding of multiple bilateral pulmonary radiographic thickening, in the absence of respiratory symptoms. The dosage of the serum anti-GM-CSF antibodies was of 284.7 mcg/ml, thus indicating an autoimmune form of the disease. Pulmonary function tests (PFT), inclusive of DLCO, were normal and chest HRCT (High Resolution Computed Tomography) scan showed a crazy paving pattern predominantly localized to the upper and middle lobe (Figure 1A). Due to the absence of symptoms or functional alterations, a clinical-radiological follow-up was suggested, without performing any specific treatment. Since then he underwent pneumological controls on regular basis, the last one performed in February 2016, confirming a complete clinical, radiological and functional stability (Figure 1B).
Case 2: 40-year-old man diagnosed with PAP, in 2004 developed progressive respiratory failure. The HRTC showed a crazy paving bilaterally spread (Figure 1C), thus he was admitted to the first WLL treatment. However, the therapeutic effects of the lavage were transitory and it was necessary to repeat the treatment procedure in February 2005 and in August 2005, again with minimal and transient benefit. Given the poor response to WLL, other non-conventional therapies were then considered. On the basis of a previous study , the patient was admitted to several sessions of plasmapheresis, in order to remove the anti GM-CSF antibodies from the patient’s plasma. The patient underwent 10 treatment sessions between February and March 2006. Unfortunately, this treatment did not improve neither the clinical condition of the patient nor the pulmonary function or chest CT (Figure 1D). After the plasmapheresis cycles, three additional WLLs have been required (March 2006, July 2006 and May 2007). Although the lung manifestations of PAP were still present, WLL therapy has been required less frequently.
Case 3: 26-year-old man, former smoker. In January 2013, following a car accident causing a chest trauma, he underwent a series of diagnostic tests, including a HRCT of the chest which showed a diffuse parenchymal lung impairment on both sides, with multiple ground-glass areas associated with smooth thickening of the interlobular septa (a “crazy paving” pattern), involving both the central and peripheral regions in all lung lobes. A diagnosis of autoimmune PAP was made on the basis of bronchial alveolar lavage fluid (BALf) cytology and anti GM-CSF antibodies measurement. In September, another functional revaluation was performed due to the appearance of chest pain associated with dyspnoea. The HRCT scan of the chest was slightly worse than the previous one (Figure 1E). The PFT showed a mild restrictive syndrome with DLCO 55% of predicted and a significant exertional desaturation on exercise, after 158 meters. The WLL was performed in October 2013. The subsequent evaluation, in April 2014, showed a marked improvement of patient’s clinical conditions and exercise tolerance (1054 meters walked on a treadmill) and a resolution of pulmonary infiltrates at the chest HRCT scan (Figure 1F). Ever since, no need for further WLL has been required.
The clinical cases here described are emblematic of a disease with a highly variable course. In autoimmune PAP, not only disease presentation is characterized by a great variability, but also the natural history of the disease is very changeable, ranging from spontaneous resolution, only in 5-10% of cases, to complete refractoriness to the treatment [6-9].
The therapeutic strategy is oriented on WLL in the major part of the cases even if, in rare cases particularly refractory to WLL, plasmapheresis has been attempted in order to reduce autoantibody levels sufficiently to improve surfactant clearance, by restoring surfactant catabolism in alveolar macrophages. Nevertheless, in most cases the standard therapy with WLL results to be effective and can lead to complete remission of the pathology. Currently, WLL represents the therapeutic standard, although it lacks from international consensus documents on the procedure and the technique is performed according to the experience of the single center. For this reason, the referral of patients to national reference centers could be helpful to gain optimal results.