Response to inhaled granulocyte‐macrophage colony‐stimulating factor in patient with mild‐to‐moderate autoimmune pulmonary alveolar proteinosis—24 months of follow‐up

Abstract Introduction Autoimmune pulmonary alveolar proteinosis (aPAP) is a disease caused by IgG antibodies against granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Whole lung lavage (WLL) allows to remove the lipo‐proteinaceous material accumulated by the poor clearance of alveolar surfactant. However, it is a complex technique that is not exempt from complications, and in some cases, the patients are refractory, requiring the performance of several WLLs spaced apart in time. Materials and Methods We present the clinical, functional, and radiological evolution after 24 months of follow‐up of a patient diagnosis of aPAP refractory to WLL, with performed three therapeutic WLLs spaced 16 and 36 months and serious potentially fatal complications in the last one. Results and Disscusion After 24 months, no adverse effects have appeared and the great clinical, functional and radiological response is maintained. The patient has been successfully treated with inhaled recombinant human GM‐CSF sargramostim.


| INTRODUCTION
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation in the pulmonary alveoli of lipoprotein material derived from pulmonary surfactant, causing alterations in gas exchange. 1The pathogenesis is related to decreased surfactant clearance due to alterations in the phagocytic capacity of alveolar macrophages. 1Three main categories of PAP have been defined depending on the etiology: autoimmune (primary or idiopathic), secondary, and genetic. 2 The treatment of choice is whole lung lavage (WLL). 2 This method removes lipo-proteinaceous material accumulated in alveoli surface by lavage to improve breath function with response rate 70%-84%. 3lassically, the procedure has been performed under a general anesthesia with rigid bronchoscope, after selective intubation and mechanical ventilation. 2Some centers used flexible fiberoptic bronchoscope (FFB) instead of selective intubation under a general anesthesia and mechanical ventilation.Yet, selective intubation and mechanical ventilation may be the cause of severe complications such as barotrauma, pneumothorax, or infections. 2,3n addition, Froudarakis et al. have reported successful and uncomplicated WLL performed by FFB in a 13-year-old girl awake under local anesthesia only, avoiding general anesthesia, selective intubation, and mechanical ventilation. 47][8] However, the duration of treatment in the literature is variable, and an optimal guideline has not yet been established.
We present the clinical, radiological, and functional evolution of a case successfully treated with inhaled GM-CSF, during 24 months of treatment.

| MATERIALS AND METHODS
A late 30s-year-old male with smoking history (21 package year) and no other risk factors of interest presents in April 2014 FVC 3570 mL (69%), FEV1 2630 mL (63%), RV 55%, TLCO53%, and KCO 69% with persistent pulmonary infiltrates suggestive of alveolar proteinosis.Clinically, the patient has moderate restrictive ventilatory impairment, moderate diffusion impairment, and moderate-severe hypoxemic respiratory failure with desaturation in the walk test that requires a chronic home oxygen therapy program.Anti-GM-CSF antibodies in serum were analyzed with a positive result: 24.6 U/mL [<5 U/mL], confirming the diagnosis of aPAP.
In the following 5 years, given the functional worsening, the patient required three therapeutic WLLs spaced 16 and 36 months apart (October 2014, February 2016, and March 2019).
In the last therapeutic WLL, the patient developed major complications that required admission to the intensive care unit (acute respiratory distress syndrome, with severe bronchospasm, need for extracorporeal membrane oxygenation, encephalopathy in the context of severe desaturation, and bilateral pulmonary thromboembolism due to thrombosis of the right jugular vein).
In October 2019 (7 months after third WLL), he presented again a rapid decline in clinical, functional, and radiological evolution (see Table 1 and Figure 1), so offlabel treatment with recombinant human sargramostim GM-CSF was chosen.
250 μg of drug was administered every 12 hours for 7 days every other week, diluted in 5 mL of saline and T A B L E 1 Clinical and functional evolution of the ventilatory parameters and the 6-min walk test.inhaled through a mouthpiece coupled to a pneumatic nebulizer according to the recommendations of the Spanish Society of Pneumology and Thoracic Surgery, 9 prior inhalation of salbutamol to prevent bronchospasm.
The authors have the written informed consent of the patient for access to their medical history and publication of the results.

| RESULTS
After 3 months of treatment, a great functional, blood gas analysis and radiological improvement was observed.The chest radiograph showed radiological improvement of the bilateral alveolar pattern, with greater aeration of the entire left hemithorax and slight clearance of the infiltrate of the right hemithorax (Figure 1).FVC F I G U R E 1 Radiological evolution (chest X-ray).Situation before third WLL, 1 further worsening after 7 months after third WLL, 2 improvement after 3 months of treatment with inhaled GM-CSF, 3 and stability after 18 months of treatment. 4ncreased 21.7%, FEV1 14.3%, TLCO 43.2%, and KCO 16.9% (Table 1).
After 18 months, the comparison of the highresolution CT (HRCT) of the chest with the baseline before treatment shows radiological improvement with clearance of bilateral parenchymal infiltrates, and the chest X-ray shows stability compared to the previous one (1 year post-treatment) as can be seen in Figure 1.On the other hand, the ventilatory parameters showed a notable improvement with a great improvement in gas exchange.In addition, for the first time, the patient did not desaturate during the 6-min walk test (Table 1).
After 24 months, no adverse effects have appeared, and the clinical response has been excellent, presenting normal total lung capacity and forced vital capacity (102% and 87%, respectively) with mild-moderate alteration of pulmonary diffusion (KCO in the limit lower than normal with slightly lower TLCO), without significant desaturation in the walk test (O 2 Sat.= 96%), radiological stability in HRCT chest, and it has been possible to withdraw the oxygen therapy that he needed for ambulation.

| DISCUSSION
We present a case treated with inhaled GM-CSF after three whole lung lavages, with major complications after the last one.The treatment has generated great satisfaction for the patient with excellent clinical, functional and radiological response with significant improvement in gas exchange, which has allowed home oxygen therapy to be withdrawn.
The pharmacy department supported off-label treatment by means of a favorable report to the regulatory agency.Also, in the absence of package leaflet, the pharmacy department prepared individualized information for the patient about the drug and treatment.
In the case presented by Rodríguez Portal et al., a 32-year-old woman who started therapy with inhaled GM-CSF after two whole lung lavages, no adverse effects appeared after 12 months of treatment, and dyspnea went from grade 3 to 1 on the Medical Research Council scale with improvement in FVC from 37% to 51% and in DLCO from 23% to 51%, with withdrawal of home oxygen therapy. 6Gajewska et al. also reported a case of a 14-year-old boy treated with inhaled GM-CSF after three whole lung lavages with clinical improvement after 17 months of treatment: FVC went from 70% to 79% and DLCO from 54% to 74%, with no adverse effects. 8s an alternative to inhaled GM-CSF therapy, after failure or contraindication of whole lung lavage, other treatments such as subcutaneous GM-CSF 250 mcg/day have been tried with similar response rates; however, unlike inhaled therapy, some mild adverse effects such as fever, fatigue, headache, and injection site complications are included.Other studies have also tested the use of the anti-CD20 monoclonal antibody rituximab; however, it was associated with risks, and some of them serious. 1,10fter 2 years of follow-up, no adverse effects have been associated with the experimental therapy, and it has allowed the patient to avoid the therapeutic WLL he had been undergoing, with only a temporary improvement and risk of associated serious complications.
In conclusion, our case supports that inhaled GM-CSF has been safe and effective in the treatment of aPAP and represents a therapeutic option after resistance or contraindication to therapeutics whole lung lavage.

AUTHOR CONTRIBUTIONS
Iv an Oterino-Moreira designed study, performed study, collected data, analyzed data, and wrote the paper.María-Jesús Linares-Asensio, Sira Sanz-M arquez, and Montserrat Pérez-Encinas analyzed data and contributed important reagents.