The Novel Use of Daratumumab in the Treatment of Refractory Autoimmune Pulmonary Alveolar Proteinosis

ABSTRACT

Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by circulating anti‐granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) auto‐antibodies that impair alveolar macrophage and neutrophil function. Macrophage dysfunction leads to accumulation of protein‐ and lipid‐rich surfactant within alveoli, impairing gas exchange and leading to respiratory failure. Standard treatments include whole lung lavage (WLL) as first‐line therapy, nebulised replacement of GM‐CSF, and in refractory cases, lymphocyte depletion, immunosuppression, or lung transplantation. We present a case of a 51‐year‐old patient with severe, treatment‐refractory aPAP failing all standard PAP therapies. A compassionate access program enabled commencement of Daratumumab, a CD38‐directed monoclonal antibody (mAb), targeting long‐lived plasma cells and providing a novel approach to treatment‐resistant autoimmune conditions. One year post completion of Daratumumab, the patient remained in remission with clinical and radiological improvement. There was a corresponding reduction in anti‐GM‐CSF antibody levels and improvement in gas exchange on pulmonary function testing.

We present a case of refractory autoimmune pulmonary alveolar proteinosis (aPAP) successfully treated with Daratumumab, a novel CD‐38 monoclonal antibody (mAb).

1. Introduction

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by circulating anti‐granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) auto‐antibodies that impair alveolar macrophage and neutrophil function [1]. The cytokine GM‐CSF is an alveolar macrophage and neutrophil growth and differentiation factor. Macrophage dysfunction leads to accumulation of lipid‐and protein‐rich surfactant within pulmonary alveoli, impairing gas exchange and increasing susceptibility to pulmonary infections.

First‐line therapeutic intervention for symptomatic patients with impaired gas exchange includes whole lung lavage (WLL), removing lipo‐proteinaceous material from the alveoli [2]. The replacement of GM‐CSF via nebulised inhalation is an effective second‐line non‐invasive therapy [3]. Many cases are controlled by these treatments although some cases remain refractory and demand escalation of treatment including lymphocyte depletion, immunosuppression or lung transplantation [4].

B‐cells are an important cell population in autoimmunity. Long‐lived plasma cells contribute to humoral autoimmunity and survive independently of antigenic stimulation in bone marrow and inflamed tissues. Plasma cells express high levels of the surface molecule CD38 and have been found to be resistant to conventional therapeutic strategies including immunosuppression and B‐cell depletion [5]. Targeting CD38 is a novel therapeutic option in refractory autoimmune diseases [5]. We present a case of refractory aPAP successfully treated with Daratumumab, a novel CD‐38 monoclonal antibody (mAb).

2. Case Report

A 51‐year‐old female presented with hypoxic respiratory failure (PaO2 58 mmHg; SpO2 92% on FiO2 55 mmHg), following a 12‐month history of progressive dyspnoea, reduced exercise tolerance (20 m), dry cough, and unintentional weight loss (10 kg). Her past history was significant for iron deficiency anaemia (IDA), hypertension, dyslipidaemia, diabetes mellitus, and obstructive sleep apnoea. Her medications included amlodipine, candesartan, metformin, ezetimibe, rosuvastatin, and omeprazole. She worked as a nurse, was a life‐long non‐smoker with significant passive smoking exposure, and denied excessive alcohol or illicit substance use. No infectious or environmental exposures were identified. She was up‐to‐date with age‐appropriate malignancy screening, including colonoscopy for IDA.

Chest HRCT demonstrated extensive bilateral pulmonary ground‐glass opacities (GGO) with interlobular septal thickening resembling a “crazy‐paving” pattern (Figure 1A). Pulmonary function testing revealed restrictive ventilatory defect (forced expiratory volume (FEV₁) to forced vital capacity (FVC) ratio of 0.82, FEV₁ 78%, FVC 72% and total lung capacity of 72% predicted), with impaired gas exchange (transfer capacity carbon monoxide (TLCO) 65% predicted). Bronchoalveolar lavage (BAL) yielded a milky‐white eluate with cytopathology revealing alveolar macrophages containing Periodic Acid Schiff‐positive intracytoplasmic granular material, confirming the diagnosis of PAP. Circulating serum anti‐GM‐CSF antibodies were markedly elevated (0.90 OD units; reference < 0.23) confirming the diagnosis of autoimmune PAP. The patient's PAP was classified as severe PAP (Severity Prognosis Score of PAP of 8) and they underwent WLL (31 L left lung, 25 L right lung) with clinical and radiological improvement (Figure 1). During initial admission, she underwent investigation for causative aetiology, with unremarkable microbiological and malignancy investigations.

FIGURE 1.

(A) Demonstrates the patient's high‐resolution CT Chest prior to WLL. (B) Demonstrates high‐resolution CT Chest post successful completion of WLL. (C) Demonstrates the bags of eluted fluid from WLL until fluid drained clear. Image 1D demonstrates the visual comparison of eluted fluid, showing the second litre drained compared to litre 30.

Within the first year post‐diagnosis, the patient was readmitted seven times for hypoxic respiratory failure, each episode marked by recurrent symptoms (dyspnoea, cough, reduced exercise tolerance, and hypoxia) and progressive GGO on HRCT chest (Figure 1). From diagnosis (March 2021) to remission (November 2023), she underwent 13 WLL, with an average lavage volume of 26.5 L on the left and 24 L on the right. Each WLL yielded short‐lived clinical and radiological improvement, with an average interval of 10 weeks between procedures. Owing to the refractory nature of her aPAP, she was treated with nebulised GM‐CSF (Sargramostim) over three courses: October 2021–March 2022, June–December 2022, and March–December 2023, Rituximab (a CD‐20 lymphocyte depleting mAb, four cycles, September–October 2021), plasmapheresis (three cycles, September 2021–May 2023), and Bortezomib (an anti‐cancer agent used to treat myeloma and lymphoma, four cycles, June–October 2022) (Figure 2). Exertional home oxygen therapy was initiated in July 2022.

FIGURE 2.

Displayed is the treatment timeline commencing from initial measurement of the patients anti‐GM‐CSF antibody levels. Anti‐GM‐CSF antibody levels as well as changes in lung function parameters (TLCO; FEV1) are shown in relation to a variety of administered treatments. Treatments highlighted included WLL, Rituximab, PLEX, nebulised‐GM‐CSF, Bortezomib and Daratumumab.

Despite multimodal B‐cell depletion and immunosuppression, she derived no sustained clinical or radiological benefit. Furthermore, no appreciable reduction was observed in anti‐GM‐CSF antibody levels or improvement in pulmonary function (Figure 2).

Daratumumab was initiated in August 2023 via a compassionate access programme and administered across 10 intravenous doses (four‐weekly cycles, followed by six‐fortnightly cycles). The patient exhibited clinical improvement following completion of Daratumumab therapy, with a decline in anti‐GM‐CSF antibody titres, reaching a nadir of 0.37 OD units (Figure 2). She has not required WLL since May 2023, nebulised GM‐CSF since December 2023, or a PAP‐related hospital admission since November 2023. One year post Daratumumab therapy, her aPAP remains in remission, with marked reduction in symptom severity, achieving an exercise tolerance of 300 m without oxygen. Chest CT showed sustained and significant improvement in GGO, and pulmonary function within normal predicted values (TLCO 98%, FEV₁ 100%).

Complications over the course of treatment involved recurrent pulmonary embolism prompting life‐long anti‐coagulation. Removal of a femoral CVC was complicated by haemorrhage secondary to a pseudoaneurysm, managed conservatively. Mycobacterium avium complex PCR was repeatedly positive on BAL, though cultures remained negative with no clinical features of active infection; thus, eradication therapy was not initiated.

3. Discussion

We present a case of a 51‐year‐old female with refractory aPAP which required multiple admissions to hospital for WLL over a two‐year period, whose course was stabilised following treatment with Daratumumab. Daratumumab is a CD‐38 mAb that targets a range of immune cells including lymphocytes, B‐cells and long‐lived plasma cells [5]. Daratumumab has been used in treatment‐refractory autoimmune conditions, including systemic lupus erythematosus, autoimmune encephalitis and ANCA‐associated vasculitis after failing or incompletely responding to Rituximab and other immunomodulatory agents [5]. It is postulated that in late stage autoimmunity, plasma cells expressing CD‐38 (CD‐20‐; CD‐38+) may be responsible for antibody production and potentially resistant to conventional immunomodulatory agents [5]. To our knowledge this is the first instance of use of Daratumumab for refractory aPAP with resultant remission. It is noted that spontaneous remission is a well‐documented outcome of aPAP; however, the temporal relationship to administration of Daratumumab and the correlating drop in circulating anti‐GM‐CSF antibodies suggest successful treatment.

Author Contributions

R.G.S., D.P., and Z.K. were heavily involved in treatment and identified the patient's case. Y.S. developed the treatment timeline. A.S. wrote the first draft. All authors were involved in review, editing, and discussion.

Ethics Statement

The authors declare that written informed consent was obtained for the publication of this manuscript and accompanying images using the consent form provided by the Journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Strong A., Sun Y., Pilcher D., Kaplan Z., and Stirling R. G., “The Novel Use of Daratumumab in the Treatment of Refractory Autoimmune Pulmonary Alveolar Proteinosis,” Respirology Case Reports 13, no. 6 (2025): e70246, 10.1002/rcr2.70246.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.