Refractory Autoimmune Pulmonary Alveolar Proteinosis Treated with Inhalational GM-CSF: A Case Report

ABBREVIATIONS USED IN THIS ARTICLE

CT = Computed tomography; ICU = Intensive care unit; OPD = Out-patient department; PAP = Pulmonary alveolar proteinosis; WLL = Whole lung lavage.

INTRODUCTION

Pulmonary alveolar proteinosis (PAP) is a rare clinical entity caused by macrophage dysfunction leading to the accumulation of lipid-rich periodic acid-Schiff (PAS)-positive material inside alveoli.¹

Three main types of PAP exist primary which can be autoimmune (most common-90%) or hereditary, secondary (to environmental factors or immune deficiencies), or congenital.²

Clinical symptomatology in PAP in adults includes insidious onset of shortness of breath with hypoxemia, cough with sputum production, and low-grade fever.³

Whole lung lavage continues to be the modality of choice to manage cases of PAP.⁴ However, in cases of refractory autoimmune pulmonary alveolar proteinosis not responding to whole lung lavage or clinically worsening, we continue to explore new modalities like inhalational granulocyte–macrophage colony-stimulating factor (GM-CSF) (sargramostim) which has shown benefits in decreasing disease recurrence and improving symptomatology.

CASE DESCRIPTION

A 40-year-old female from New Delhi, a non-smoker with no history of tuberculosis or heart disease was referred from the Out-Patient Department (OPD) with a saturation of 64% and insidious onset shortness of breath with productive cough. She is a trans-bronchial biopsy and anti-GM-CSF antibody (Fig. 1) proven case of autoimmune pulmonary alveolar proteinosis (anti-GM-CSF samples sent to Cincinnati, USA which came as highly positive-46.1 µg/mL). She has a history of three whole lung lavage therapies in the past 3years which each time improved her symptoms.

Her arterial blood gas showed pH-7.43, pCo2-35 mm Hg, HCO3-23.2 meq/L and lactate of 1.2 meq/L.

In the emergency room, she was nebulized with salbutamol and budesonide, given hydrocortisone 200 mg and an injection of furosemide 20 mg IV which stabilized the symptoms of the patient.

On examination, general condition of the patient was sick with bi-basal crackles and diffuse wheeze in all of lung fields and a respiratory rate of 26/minute.

Chest X-ray showed bilateral filling opacities (Fig. 2) in mid to lower zones and the computed tomography (CT) scan showed diffuse bilateral ground glass opacities showing a recurrence of the disease process.

The patient was shifted to the medical ICU for further management and stabilization where she was nebulized with formoterol plus budesonide combination inhalation along with other supportive care.

Extensive investigations were carried out including upper respiratory biofire (no organism found), urine routine microscopy, urine cultures, and full blood counts all of which were normal.

This time with an aim to reduce recurrence, improve symptoms, and decrease long-term oxygen therapy, the patient was started on inhalational GM-CSF (125 µg with 4 mL normal saline nebulization).

This to our pleasant surprise showed significant improvement with a decrease in infiltrates on chest X-ray and a decrease in diffuse ground glass opacities in both lung fields.

The patient was subsequently discharged with inhalational GM-CSF at a dose of 125 µg twice daily for 7 days, every other week and long-term low-flow oxygen therapy to decrease the risk of recurrence and has since shown no signs of disease progression.

DISCUSSION

Autoimmune pulmonary alveolar proteinosis is an extremely rare entity encountered in respiratory medicine clinical practice, resulting in accumulation of surfactant (lipid rich material) inside the alveoli. This occurs mainly due to autoimmune mechanism (90%), due to antibodies against GM-CSF resulting in defecting clearance of surfactant by the macrophages inside the alveoli.³

This case is unique because it provides insights into the management of patients with refractory autoimmune pulmonary alveolar proteinosis using a new and upcoming strategy of inhalational GM-CSF. This therapy will target autoimmune pulmonary alveolar proteinosis at its root cause of GM-CSF and help in the resolution of symptoms (improve paO2 and pA-aO2 gradient) and decrease chances of recurrence.⁵

Current literature suggests whole lung lavage (WLL) as a definite first-line treatment in the management of autoimmune pulmonary alveolar proteinosis.³

It’s high time we think beyond whole lung lavage as the recurrence chances are high causing distress to the patient and use of valuable resources. Thus comes the role of inhalational GM-CSF which has shown in recent texts of research, significant improvement in alveolar -arterial oxygen gradient. However which route is preferred and causes more improvement in patients is still a matter of debate however recent studies have shown inhalational GM-CSF to be superior to the subcutaneous mode of administration.⁵

Based on the results of our patient and the studies showing the remarkable difference in patients using inhalational GM-CSF it a very promising tool in managing cases of refractory autoimmune pulmonary alveolar proteinosis.

CONCLUSION

Refractory autoimmune Pulmonary alveolar proteinosis has been the focus of interest for pulmonologists for a long time due to the unsolved mystery of tackling the autoantibodies against GM-CSF and we believe that inhalational GM-CSF has the capability to solve this problem in PAP. It has been shown in our case to decrease symptoms, need for long-term oxygen therapy, and repeated need for whole lung lavage. In the times to come, it should be incorporated as an important line of defense against refractory autoimmune pulmonary alveolar proteinosis to improve the quality of life in patients and give them a chance at beating this rare but serious disease entity.

REFERENCES

1. Yu Hy, Sun Xf, Wang Yx, et al. Whole lung lavage combined with Granulocyte-macrophage colony stimulating factor inhalation for an adult case of refractory pulmonary alveolar proteinosis. BMC Pulm Med 2014;14:87. DOI: 10.1186/1471-2466-14-87.

2. Khan A, Agarwal R. Pulmonary alveolar proteinosis. Respir Care 2011;56(7):1016–1028. DOI: 10.4187/respcare.01125.

3. Suzuki T, Trapnell BC. Pulmonary alveolar proteinosis syndrome. Clin Chest Med 2016;37(3):431–440. DOI: 10.1016/j.ccm.2016.04.006.

4. Keske A, Destrampe EM, Barksdale B, et al. Pulmonary alveolar proteinosis refractory to plasmapheresis and rituximab despite GM-CSF antibody reduction. Case Rep Immunol 2022;2022:2104270. DOI: 10.1155/2022/2104270.

5. Sheng G, Chen P, Wei Y, et al. Better approach for autoimmune pulmonary alveolar proteinosis treatment: Inhaled or subcutaneous granulocyte-macrophage colony-stimulating factor: A meta-analyses. Respir Res 2018;19(1):163. DOI: 10.1186/s12931-018-0862-4.