Dr. Ilaria Campo
Laboratorio di Biochimica e Genetica
Fondazione IRCCS Policlinico San Matteo, Pavia
In the beautiful framework of London, we attended the ERS International Congress. It was a fruitful opportunity for the PAP network to share information and updates on the disease and its treatment.
In particular, abstracts regarding PAP were presented during an oral presentation session on the advancements in bronchoscopy, a poster discussion session on paediatric bronchology and a thematic poster session on orphan diseases.
Whole Lung Lavage (WLL) remains the gold standard for PAP treatment, however it is not a standardized procedure.
The WLL International Study group (Campo et al.) reported the results of a global survey of current practice and procedure, which involved centers performing WLL in either pediatric and/or adulthood setting. They collected expert opinions from 20 centers in 14 countries performing WLL in adults and 10 centers in 6 countries performing WLL in pediatric patients. The aim of the survey was to obtain a real life picture as most exhaustive as possible on indications and contraindications, technology, modifications, outcome, and complications of WLL as performed in different centers from different countries. Such information could be useful in formalizing a consensus document. An ad hoc task force is therefore advisable.
At the same time, the French-Speaking Endoscopy Group (GELF) (Gay et al.) tried to assess the efficacy of WLL in PAP patients. They included 11 centers and collected data concerning patient’s and disease characteristics, pulmonary function tests (PFTs) before and after the procedure, and technical information on the procedure. They found a significant improvement in patients’ short-term respiratory condition, in particular PaO2. However, long-term effect needs to be confirmed, as many of their patients relapsed.
The Spanish group (Iglesias et al.) reported the case of a toddler (21-month-old girl) affected by secondary PAP, who needed WLL treatment. At the age of 7 months she was diagnosed with myeloblastic leukemia. After no response to chemotherapy, she underwent hematopoietic stem cell transplant. PAP was diagnosed at the age of 20 months, when she experienced respiratory distress and persistent hypoxemia.
A WLL was done, using simultaneously 2 endotracheal cuffed tubes: one (3.5 mm diameter) placed in the trachea to ventilate one lung and another of 3 mm to instill heated saline into the bronchus to perform the lavage. The procedure was well tolerated with a good clinical response.
The intimate mechanism regulating the WLL outcome is still unclear, thus the Japanese group (Sugimoto et al.) tried to clarify the prognostic factors after WLL in autoimmune PAP, especially focusing on serum biomarkers. They measured serum biomarkers levels (KL-6, SP-D, SP-A, CEA, CYFRA, anti GM-CSF autoantibody) before (baseline levels) and one month after WLL, in 21 patients treated by WLL. Interestingly, they found that the difference between CEA and CYFRA levels, before and after WLL, can predict the efficacy of WLL and the relapsing after WLL.
Although WLL remains the gold standard for PAP treatment, the results of the first randomized trial with WLL followed by inhaled GM-CSF (Sargramostim), performed by the Italian group (Campo et al.) with the collaboration of Prof. M. Griese from Munich and Prof. BC Trapnell from Cincinnati, and supported by the Italian Medicine Agency (AIFA), demonstrated that inhaled sargramostim is well tolerated and effective in autoimmune PAP and that combination therapy is more effective than WLL alone.
The sargramostim was administered by AKITA 2 nebulizer (Vectura) according to the following scheme: sargramostim (250 mcg/day every other week for 12 weeks followed by 250 mcg/day on 2 consecutive days every 2 weeks for 6 months).
The Italian group (Mariani et al.) showed also that inhaled GM-CSF is efficacious not only in case of progressing disease but also in case of persistence/stabilization, in order to increase response rate. They reported the case of a patient refractory to plasmapheresis combined with multiple WLLs (n=6), who experienced a substantial clinical, functional and radiological benefit after 9-months treatment (250 mcg/day every other week for 12 weeks, then 250 mcg/day on 2 consecutive days every 2 weeks for 6 months) with inhaled GM-CSF (Sargramostim).
The first randomised, double-blind, placebo-controlled, international trial in patients with autoimmune PAP treated by inhaled GM-CSF (Molgramostim) has been also presented by F. Bonella. This trial, supported by Savara Inc., will enroll 51 patients in 12 Countries in Europe, Russia, Israel and Japan and will evaluate the efficacy and safety of molgramostim in autoimmune PAP patients, who will be randomized to once daily treatment for 24 weeks with: 1) inhaled rhGM-CSF (300 µg); 2) inhaled rhGM-CSF (300 µg) or placebo administered intermittently (7 days on/7 days off); or 3) inhaled placebo. After the double-blind period, patients will enter a 48 week open-label follow-up period. WLL will be used as rescue therapy.
Finally, the Japanese group (Inoue et al.) established a consecutive nation-wide registration system for PAP in Japan, providing updated annual epidemiological data and effective surveillance data.
A total of 903 cases were registered. They reported an incidence and a prevalence of 0.69/million/year and 6.11/million, respectively. PAP were classifications subdivided into 92.9% autoimmune, 6.1% secondary, 0.4% congenital and 0.6% unclassifiable PAP. Surveillance for the intractable cases (dead, complications such as ILD, infection, etc.) was conducted via the system.