Autoimmune pulmonary alveolar proteinosis developed during treatment for systemic sclerosis: a case report

Abstract

Background

Reports of autoimmune diseases coexisting with autoimmune pulmonary alveolar proteinosis (autoimmune PAP; APAP) are extremely rare. APAP coexisting with autoimmune diseases may often be misdiagnosed as connective tissue disease–associated interstitial lung disease (ILD). Here, we describe a rare case of a patient with systemic sclerosis who was diagnosed with APAP after the exacerbation of lung opacities during treatment with immunosuppressive agents.

Case presentation

A 72-year-old woman was diagnosed with systemic sclerosis (SSc) at the age of 68, and initiated treatment with prednisolone (PSL). At the age of 70, she was diagnosed with ILD associated with SSc. Despite intravenous cyclophosphamide (IVCY), no improvement was observed. A significant elevation of Krebs von den Lungen-6 (KL-6) and a crazy-paving pattern on chest computed tomography (CT) are observed. Bronchoscopy showed milky white bronchoalveolar lavage fluid (BALF) and histology of periodic acid-Schiff (PAS) stain-positive eosinophilic granular material. Serum anti granulocyte–macrophage colony-stimulating factor (GM-CSF) antibodies were measured, and the result was positive, leading to the diagnosis of APAP.

Conclusion

In patients with interstitial lung shadows who do not improve with immunosuppressive treatment, PAP is one of the differential diagnoses that should be considered. All physicians should be aware that the appropriate diagnosis of PAP and the measurement of serum anti-GM-CSF antibodies will critically affect patient outcomes.

Background

The association of autoimmune pulmonary alveolar proteinosis (APAP) with known autoimmune diseases has remained unknown. The complication rate of autoimmune disease in APAP, which accounts for 90% of PAP, has been reported to be 1.4–1.6% [1, 2]. Here, we report a case of APAP that developed during treatment with prednisolone (PSL) for systemic sclerosis (SSc) and worsened with intravenous cyclophosphamide (IVCY) therapy.

Case presentation

In May 2023, a 72-year-old female patient was referred to our department due to exertional dyspnea. At the age of 68, she began to notice swelling in the hands and feet. Based on the findings of skin hardening extending beyond the fingers and toes, along with consistent histopathologic findings from a skin biopsy, the rheumatology department of her previous hospital diagnosed her as having SSc, despite the fact that various autoantibodies characteristic of scleroderma were negative. Steroid therapy (PSL 20 mg/day) was initiated, and the dosage was gradually tapered off as the cutaneous symptoms improved. Since the initiation of PSL treatment, the patient had been experiencing exertional dyspnea without apparent lung shadows (Fig. 1a). Two years later, an elevated Krebs von den Lungen-6 (KL-6, 2257 U/mL) and diffuse ground-glass opacities in the bilateral lung fields on chest computed tomography (CT) led to a diagnosis of interstitial lung disease (ILD) associated with SSc (Fig. 1b). Despite repeated IVCY and steroids, there was no improvement in subjective symptoms or imaging findings (Fig. 1c); at this point, she was referred to us.

Fig. 1

Chest CT progress. No opacities at diagnosis of SSc (a), mild reticular opacities and ground-glass opacities at diagnosis of ILD associated with SSc (b), reticular opacities and ground-glass opacities with no improvement after IVCY (c), progressive reticular opacities and ground-glass opacities upon admission to our department (d,e), mild improvement at 7 months after initiating oxygen therapy (f). Reticular opacities and ground-glass opacities, which were not observed at the time of SSc diagnosis, appeared over time and worsened with little improvement noted with IVCY. Seven months after initiating oxygen therapy, mild improvement in the shadows was noted

Saturation of percutaneous oxygen (SpO₂) on room air was around 90% and dropped easily into the 70% range with mild exertion. Arterial blood gas analysis revealed an arterial oxygen partial pressure of 56.0 Torr and an arterial carbon dioxide partial pressure of 34.0 Torr, indicating type I respiratory failure. Respiratory sounds were heard as extensive fine crackles in the bilateral lung fields. Blood tests showed that lactate dehydrogenase (LD) was 303 U/L (reference range: 124–222 U/L), and KL-6 was significantly elevated at 11626 U/mL (reference range: < 500 U/L). Tests related to infectious diseases showed negative results. The blood test findings are shown in Table 1, and the pulmonary function test results are presented in Table 2.

Table 1 Summary of the patient’s laboratory data

Table 2 Summary of the patient’s pulmonary function test

Chest CT revealed a mixture of ground-glass opacities and reticular shadows, as well as interlobular septal thickening in the bilateral lung fields—in other words, a crazy paving pattern, with subpleural regions relatively spared (Fig. 1d, e). Possible differential diagnoses included the progression of SSc-ILD, opportunistic infections, pulmonary edema, and PAP. However, the lack of response to previous treatments, including IVCY, the absence of symptoms such as fever or cough, low levels of β-D-glucan (BDG), and the absence of physical findings such as lower extremity edema or orthopnea led us to strongly suspect PAP. Consequently, a bronchoscopy was performed to confirm the diagnosis. Bronchoalveolar lavage (BAL) was obtained from the right B5, and biopsies were taken from the right B3, B4, and B8. The bronchoalveolar lavage fluid (BALF) yielded 103/160 mL (64% recovery) and appeared as a milky-white fluid (Fig. 2a). The cell count was 1.1 × 10⁵/mL, with the cellular fraction showing a predominance of macrophages (70%), lymphocytes (24%), neutrophils (4%), and eosinophils (2%). Histopathologic examination of the biopsy specimen stained with hematoxylin and eosin (HE) revealed the presence of eosinophilic granular material filling the alveolar spaces (Fig. 2b). The same material was positive for periodic acid–Schiff (PAS) staining (Fig. 2c).

Fig. 2

Histopathological and BALF findings. The BALF had a milky-white appearance typical of PAP (a). Histopathological examination revealed the presence of eosinophilic granular material filling the alveolar spaces on HE staining (b). The same material stained positive with PAS staining (c)

Based on the above findings, we diagnosed the patient with PAP. Anti granulocyte–macrophage colony-stimulating factor (GM-CSF) antibodies in the serum were positive at 86.4 µg/mL (cutoff value 1.0 µg/mL), leading to the diagnosis of APAP. With a disease severity score (DSS) of 4, lavage treatments such as whole lung lavage (WLL) were considered. However, due to the presence of concomitant Alzheimer's-type presenile dementia, the high risk associated with these treatments was deemed unfavorable. As exertional dyspnea and SpO₂ had improved with oxygen therapy, she was discharged with the initiation of home oxygen therapy (2L at rest, 4L on exertion). Seven months after the diagnosis of APAP, mild improvement was observed in imaging findings (Fig. 1f). The oxygen requirement has remained unchanged, and her progress is being monitored by outpatient follow-ups.

Discussion and conclusion

We encountered a case of APAP that developed during immunosuppressive treatment for SSc. As far as we have determined, there has been only one case report of APAP coexisting with SSc [3]. In autoimmune disease patients, both APAP and secondary pulmonary alveolar proteinosis (SPAP) could develop [4,5,6]. As stated in the background section, the complication rate of autoimmune disease in APAP has been reported to be 1.4–1.6%, and autoimmune disease as a cause of SPAP is estimated to be 7% [7]. We can speculate that APAP is the most common form of PAP in these patients. On the other hand, there is no available data on the frequency of PAP in patients with autoimmune diseases as most cases had been published as case reports. In those reports, various autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and ANCA-associated vasculitis, have been reported to coexist with APAP [8,9,10].

Anti-GM-CSF antibodies are present at low levels in healthy individuals, and approximately 99% of these antibodies are neutralized by binding to GM-CSF [11]. There is report of elevated plasma GM-CSF levels in patients with localized scleroderma [12]. In addition, in preclinical models, cyclophosphamide impairs endothelial cells and alveolar epithelial cells in lung vascular bed, leading to the accumulation of neutrophils and causing morphological changes resembling endogenous lipoid pneumonia or PAP [13]. Based on the above findings, in our case, we can speculate the following hypothesis of etiology. First, SSc-related inflammation leads to overproduction of GM-CSF, and that serum anti-GM-CSF antibodies are elevated secondary to neutralize the increased GM-CSF. The use of PSL for the disease control of SSc results in substantial decrease in GM-CSF, and relative excessive anti-GM-CSF antibodies finally develop APAP. A comparison of our case with previously reported Yamasue’ case [3] is shown in Table 3.

Table 3 Comparative analysis of cases of APAP complicated by SSc

In both cases, clinical manifestation of APAP occurred more than one year after the onset of SSc treatment and under immunosuppressive therapy. This may support our hypothesis and APAP can occur with steroid monotherapy alone, immunosuppressive drugs such as IVCY or tacrolimus further facilitate exacerbation of APAP. Currently, how the presence or absence of PAP could affect the prognosis of SSc remains elusive, but given the probable risk of respiratory failure, appropriate treatment should be administered to patients with PAP, separately from therapies with SSc.

In 2024, sargramostim inhalation therapy for APAP was approved in Japan for the first time in the world. This is based on the results of two phase III studies in Japan and overseas that showed that the inhalation of GM-CSF significantly improves gas exchange capacity by promoting maturation of alveolar macrophages and the consequent degradation of lung surfactants [14, 15]. The treatment of APAP is, thus, expected to progress greatly in the future based on the emergence of this novel therapy.

When interstitial shadows appear in patients with autoimmune diseases, as in this case, they can be diagnosed as collagen-related interstitial pneumonia, and treatment with steroids or immunosuppressive agents will be initiated. As a result, in the case of APAP, the diagnosis would be made after the apparent worsening of lung field shadows and the manifestation of a crazy paving pattern, which could delay the initiation of treatment for APAP, including whole-lung lavage and sargramostim inhalation.

In summary, when an interstitial shadow is observed during the course of an autoimmune disease, respiratory physicians should suspect the possibility of PAP, perform bronchoscopy for BAL in cooperation with the department in charge, and measure anti-GM-CSF antibodies to diagnose APAP.