The Indian Journal of Chest Diseases and Allied Sciences
Volume 65 | Issue 3 | Year 2023

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

Sandeep Nayar1, Imaad Rahman2, Sunny Kalra3, Manish Garg4, Shreshth Nayar5

1,3,4Department of Respiratory Medicine, BLK-MAX Super Speciality Hospital, New Delhi, India

2Royal Blackburn Teaching Hospital, East Lancashire Hospitals NHS Trust, Blackburn, England

5MS Ramaiah Medical College & Hospital, MSR Nagar, Mathikere, Bengaluru, India

Corresponding Author: Sandeep Nayar, Department of Respiratory Medicine, BLK-MAX Super Speciality Hospital, New Delhi, India, Phone: +91 9810006781, e-mail:

How to cite this article: Nayar S, Rahman I, Kalra S, et al. Refractory Autoimmune Pulmonary Alveolar Proteinosis Treated with Inhalational GM-CSF: A Case Report. Indian J Chest Dis Allied Sci 2023;65(3):160–162.

Source of support: Nil

Conflict of interest: None

Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.

Received on: 20 November 2023; Accepted on: 26 December 2023; Published on: 05 February 2024


Aim and background: Pulmonary alveolar proteinosis is a rare entity with definite evidence to show symptomatic improvement with whole lung lavage therapy. Refractory autoimmune pulmonary alveolar proteinosis continues to be a mystery as upcoming treatment modalities still show variable results.

Case description: We hereby present a case of a 40-year-old female who presented with acute severe shortness of breath with a cough for 3–4 days and was a transbronchial biopsy-proven case of pulmonary alveolar proteinosis. On admission to intensive care unit (ICU), the patient was started on inhalational granulocyte–macrophage colony-stimulating factor (GM-CSF).

Conclusion: Starting a patient on inhalational GM-CSF provided significant clinical improvement with a decrease in dependence on long-term oxygen therapy thus showing the value of this possible treatment in managing refractory autoimmune pulmonary alveolar proteinosis.

Clinical significance: This case highlights the importance of inhalational GM-CSF therapy as a treatment modality for refractory autoimmune pulmonary alveolar proteinosis.

Keywords: Case report, GM-CSF, Ground glass opacities, Pulmonary alveolar proteinosis.


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


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.


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.

Fig. 1: Chest X-ray of the patient with pulmonary alveolar proteinosis showing bilateral bibasal infiltrates

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.

Fig. 2: Laboratory report sent to USA for anti GM-CSF antibody titers which came back very high, suggesting autoimmune pulmonary alveolar proteinosis

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.


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.


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.

Clinical Significance

For a unique yet life-threatening disease like pulmonary alveolar proteinosis, inhalational GM-CSF can be a game changer and provide insights into the management of the disease like never before.


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.

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