Diagnostic Dilemma in a Case of Anti‐PL‐7 Antibody‐Positive Interstitial Lung Disease: When Autoimmune Alveolar Proteinosis Masquerades as Anti‐Synthetase Syndrome

ABSTRACT

Pulmonary alveolar proteinosis (PAP) and anti‐PL‐7 antibody‐positive interstitial lung disease (ILD) share early radiographic similarities, yet their treatments differ significantly. This article reports a rare case of dual anti‐PL‐7 and anti‐GM‐CSF autoantibody positivity, initially misdiagnosed as anti‐synthetase syndrome due to interstitial infiltrates and concurrent Nocardia/Aspergillus infections. Empirical glucocorticoid therapy worsened symptoms. Definitive PAP diagnosis was confirmed via milky bronchoalveolar lavage fluid (BALF) and anti‐GM‐CSF autoantibody detection, alongside incidental pulmonary embolism. Multidisciplinary intervention (antimicrobials, thrombolysis, and whole‐lung lavage) improved oxygenation. Clinicians must consider PAP as a differential diagnosis in patients with atypical presentations before commencing immunosuppressive therapy. Multidisciplinary collaboration is crucial for managing complex PAP cases.

Pulmonary alveolar proteinosis (PAP) and anti‐PL‐7 antibody‐positive interstitial lung disease (ILD) share early radiographic similarities, yet their treatments differ significantly. This article reports a rare case of dual anti‐PL‐7 and anti‐GM‐CSF autoantibody positivity, initially misdiagnosed as anti‐synthetase syndrome due to interstitial infiltrates and concurrent Nocardia/Aspergillus infections. Definitive PAP diagnosis was confirmed via milky bronchoalveolar lavage fluid (BALF) and anti‐GM‐CSF autoantibody detection, alongside incidental pulmonary embolism. This case demonstrates diagnostic pitfalls and therapeutic paradoxes arising from cross‐positivity of these antibodies.

1. Introduction

Pulmonary alveolar proteinosis (PAP), a rare disease characterised by abnormal lipoproteinaceous material accumulation in alveoli, is mediated by anti‐granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) antibodies in 90% of autoimmune PAP cases [1]. The anti‐PL‐7 antibody (anti‐threonyl‐tRNA synthetase antibody), a specific marker for anti‐synthetase syndrome (ASS), is frequently associated with rapidly progressive interstitial pneumonia (RP‐ILD) through immune‐mediated alveolar‐capillary injury pathogenesis [2]. However, both conditions may present with similar interstitial changes on imaging while requiring divergent therapeutic strategies: ASS necessitates immunosuppressive therapy, whereas steroid administration in PAP patients may exacerbate alveolar macrophage dysfunction and clinical deterioration [1, 2]. This case demonstrates diagnostic pitfalls and therapeutic paradoxes arising from cross‐positivity of these antibodies.

2. Case Report

A 56‐year‐old female was admitted to the hospital in July 2024 due to persistent cough and shortness of breath for 2 weeks. She has no family history of autoimmune diseases, no history of smoking, and no occupational exposure to dust. Chest computed tomography (CT) examination revealed interstitial changes in both lungs accompanied by patchy exudation and mild enlargement of mediastinal lymph nodes (Figure 1A). The results of bronchoalveolar lavage fluid (BALF) metagenomic sequencing (NGS) confirmed the presence of Wallace Nocardia infection (45,996 reads, relative abundance 61%), and head MRI suggested brain abscess (Figure 1G). Laboratory tests revealed elevated levels of tumour markers, carcinoembryonic antigen (10.80 ng/mL) and cytokeratin 19 fragment (6.65 ng/mL). After treatment with triple antibiotics compound sulfamethoxazole + levofloxacin + ceftriaxone, symptoms improved. After discharge, the patient continued oral administration of compound sulfamethoxazole combined with linezolid for anti‐infection treatment and was supplemented with long‐term home oxygen therapy.

FIGURE 1.

Dynamic evolution of the patient's pulmonary imaging: (A) The initial chest CT scan shows diffuse interstitial changes in both lungs accompanied by patchy ground‐glass opacities, and mild enlargement of the mediastinal lymph nodes. (B) Two months later, the re‐examination shows a reduction in the solid nodules in both lungs, but an increase in interstitial exudation in the lower lobes. (C) After misdiagnosis of RP‐ILD and treatment with glucocorticoids plus voriconazole, a typical ‘road‐paving stone sign’ with small interlobular septal grid‐like thickening is observed. (D) After total lung lavage, the lesions show significant absorption. (E, F) After sequential GM‐CSF nebulisation treatment for 1 and 3 months, the exudation improves progressively. Diagnosis and treatment process of combined intracranial Nocardia infection. (G) The initial enhanced MRI scan shows a ring‐shaped enhanced abscess in the right parietal lobe (arrow). (H) After 2 months of treatment with sulphonamides combined with linezolid, the lesion is absorbed. Figure (I) shows PAS staining (+), suggesting glycoprotein deposition (arrow).

On 11 September 2024, the patient's condition deteriorated, with chest tightness and shortness of breath worsening. Chest CT showed a reduction in multiple solid nodules in both lungs, but increased interstitial exudation in the lower lobes (Figure 1B). Cranial MRI showed resolution of the abscess lesion (Figure 1H). Bronchoscopy revealed a large amount of white sputum‐like secretions in the bronchi of both lobes. BALF‐NGS detected a delayed Aspergillus infection (133 reads, abundance 34.59%), while serum PL‐7 antibody was definitively positive by immunoblotting. This combination led to a misdiagnosis of anti‐synthetase syndrome‐related rapidly progressive interstitial lung disease. The patient received glucocorticoid pulse therapy, immunoglobulin and voriconazole treatment. The symptoms improved briefly.

However, on 25 November 2024, the patient's condition progressed again, with exacerbated chest tightness and shortness of breath. Chest CT showed a typical ‘roadblock sign’ with thickening of the interlobular septa (Figure 1C), and BALF was milky and PAS staining was positive (Figure 1I). Serum anti‐GM‐CSF antibody was significantly elevated (> 274.2 U/mL), and the patient was ultimately diagnosed with PAP and was found to have extensive pulmonary artery embolism and deep vein thrombosis in the lower extremities (D‐dimer 4.68 μg/mL). Systolic pulmonary artery pressure reached 42 mmHg. On 1 December 2024, the patient received multidisciplinary comprehensive intervention, including inferior vena cava filter placement, pulmonary thrombolysis treatment, anticoagulation therapy, and whole lung lavage combined with GM‐CSF nebulisation treatment. After treatment, the oxygenation index significantly improved from 116 to 244 mmHg. CT examination showed lesion absorption (Figure 1D), and the condition was effectively controlled. After discharge, the patient received sequential GM‐CSF nebulisation therapy for 3 months, showing progressive improvement in exudation at both 1 and 3 months post‐treatment (Figure 1E,F).

3. Discussion

Acquired pulmonary alveolar proteinosis, primarily autoimmune PAP, accounts for 90% of cases and is characterised by macrophage dysfunction due to anti‐GM‐CSF antibodies, leading to impaired surfactant clearance. This immune dysregulation predisposes patients to opportunistic infections, such as Nocardia and Aspergillus, which may precede PAP diagnosis by months. Serum biomarkers, including carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21‐1), krebs von den Lungen‐6(KL‐6), and lactate dehydrogenase (LDH), are valuable in assessing disease activity and predicting treatment response [1]. Thus, PAP should be suspected in patients with diffuse alveolar infiltrates, opportunistic infections, and abnormal serum markers.

This case highlights the diagnostic challenges of PAP, particularly when coexisting with anti‐PL‐7 antibodies, a hallmark of ASS. The patient presented with Nocardia and Aspergillus infections, elevated CEA, and bilateral interstitial changes, initially misdiagnosed as ASS due to overlapping imaging features with RP‐ILD. The absence of typical ASS symptoms, such as myositis or mechanic's hands, and the lack of chylous BALF and anti‐GM‐CSF antibodies delayed the diagnosis. Anti‐PL‐7 antibody‐positive interstitial lung disease typically responds well to steroids, but in this case, steroid therapy exacerbated PAP, likely due to suppressed alveolar macrophage function and increased surfactant production. Furthermore, corticosteroids may impair granulocyte and macrophage bactericidal activity, increasing infection risk [3].

The coexistence of anti‐GM‐CSF and anti‐PL‐7 antibodies in ILD is rare, and its mechanism remains unclear. Currently, anti‐PL‐7 antibody‐positive PAP remains sparsely reported. Hiroshi Ishimoto et al. [4] documenting a rare case initially misdiagnosed as anti‐ARS antibody‐associated interstitial pneumonia. Environmental factors, such as viral infections or dust exposure, may induce conformational changes in aminoacyl‐tRNA synthetases, triggering anti‐PL‐7 antibody production and subsequent alveolar inflammation and fibrosis [5]. This case underscores the importance of differentiating PAP from ASS, especially when steroid therapy fails. GM‐CSF antibody testing and BALF analysis should be routine in such scenarios.

Complications, including pulmonary embolism and deep vein thrombosis, further complicated treatment. Although rare, thrombosis in PAP patients necessitates vigilance. Multidisciplinary collaboration among respiratory medicine, rheumatology, radiology, and critical care is essential for managing complex PAP cases, optimising outcomes, and improving patient survival and quality of life.

In conclusion, vigilant work‐up is required in patients with atypical presentations of interstitial lung disease, despite the presence of PL‐7 antibody. Multidisciplinary management of concurrent infections, thrombosis, or respiratory failure is critical, integrating antimicrobials, thrombolysis, and whole‐lung lavage for optimal outcomes of PAP and its associated complications.

Author Contributions

Beili Liu and Chao Xu drafted the initial manuscript. Yuqian Liu and Runze Song conducted data acquisition, while Fanqi Wu and Danbei Diwu contributed clinical imaging data. All authors participated in data interpretation, provided critical revisions to the manuscript for intellectual content; all authors reviewed and approved the final version for publication.

Ethics Statement

This case report was conducted in accordance with ethical principles in medical research and with the patient's written informed consent using the patient consent form provided by the Journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.