Secondary Pulmonary Alveolar Proteinosis Complicated by Hemophagocytic Syndrome in a Patient with Adult-onset Still's disease: A Case-based Review

Abstract

Treatment of secondary pulmonary alveolar proteinosis (SPAP) focuses on managing the underlying disease, typically myelodysplastic syndrome. However, immunosuppressive therapy may worsen the condition in autoimmune disease-associated SPAP. We report the case of a 74-year-old woman with hemophagocytic syndrome and adult-onset Still's disease, who developed ground-glass opacities and consolidations during immunosuppressive treatment. SPAP was confirmed by a biopsy and negative for anti-granulocyte-macrophage colony-stimulating factor antibodies. Although whole-lung lavage was considered if SPAP worsened significantly, no further deterioration was observed with tapering of prednisolone. A literature review and details of this case highlight the importance of attenuating immunosuppressive therapy, rather than its intensification, for SPAP in autoimmune diseases.

Introduction

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of surfactants in alveoli, resulting in respiratory impairment (1). Alveolar lavage and granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy are effective for autoimmune PAP (APAP), which is characterized by the presence of anti-GM-CSF antibodies (2,3). Secondary PAP (SPAP) is associated with hematologic or collagen tissue diseases (CTD), and prioritizing the management of the underlying disease is recommended, primarily based on case series studies involving myelodysplastic syndrome (MDS) (4). However, there are few studies on the treatment of SPAP associated with CTD (CTD/SPAP).

We herein report a case of SPAP complicated by hemophagocytic syndrome (HPS) due to adult-onset Still's disease (AOSD) and provide a literature review of CTD/SPAP.

Case Report

A 74-year-old woman with suspected HPS associated with AOSD was admitted to our hospital. Following a 2-week history of a persistent fever (39°C), fatigue, loss of appetite, and erythema on her face and limbs, she was previously admitted to another hospital. Laboratory findings at that institution were as follows: aspartate transaminase (AST), 121 U/L; alanine transaminase (ALT), 52 U/L; lactate dehydrogenase (LDH), 1,122 U/L; C-reactive protein 18.6 mg/dL, and serum ferritin, 25,000 ng/mL. Computed tomography (CT) showed hepatosplenomegaly without lymphadenopathy (Fig. 1a). She was tentatively diagnosed with AOSD, and tocilizumab (162 mg/week) was initiated at another hospital without glucocorticoids (GCs), considering her history of diabetes mellitus and angina. Despite this treatment, her fever persisted, and her platelet (PLT) count decreased from 366,000 to 68,000 /μL, which led to a 3-day course of methylprednisolone pulse therapy before she was transferred to our hospital.

Figure 1.

a) Upon admission to our hospital, the patient exhibited red to dark-purple rashes accompanied by pruritus and desquamation, primarily on the anterior chest and abdomen, extending to the face and limbs. b) Computed tomography (CT) performed during the previous hospitalization revealed hepatosplenomegaly, with no abnormal findings in the lungs.

On admission to our hospital, the patient was alert and oriented, and her body temperature, heart rate, blood pressure, and peripheral oxygen saturation in room air were 37.1 °C, 97 bpm, 132/73 mmHg, and 98%, respectively. Lymphadenopathy in the head, neck, and axillary regions; pharyngitis; and joint pain were absent. Persistent pruritic maculopapular rashes, ranging in color from bright red to brownish red, were observed on the limbs and trunk (Fig. 1b).

Laboratory findings revealed the following: white blood cell (WBC) count, 38,600 /μL; neutrophil fraction, 82%, hemoglobin 8.3 g/dL, PLT 85,000 /μL; AST, 117 U/L; ALT, 61 U/L; LDH, 3,035 U/L; triglycerides, 224 mg/dL; serum ferritin, 41,684 ng/mL; soluble interleukin-2 receptor (sIL-2R) 8,616 U/mL, interleukin-6 2,511 pg/mL; rheumatoid factor ＜4.0 IU/mL, and antinuclear antibodies ＜1:40. Repeated skin biopsies revealed lymphocytic infiltration around the blood vessels at the epidermal-dermal junction and in the superficial dermis, but no clear malignant findings were observed. Repeated bone marrow biopsies demonstrated hemophagocytosis, but no evidence of atypical cells was found (Fig. 2).

Figure 2.

a) A bone marrow examination revealed macrophages phagocytizing blood cells. b) A transbronchial lung biopsy revealed the accumulation of eosinophilic proteinaceous material in some alveolar spaces (arrow).

Based on her fever, splenomegaly, bicytopenia, hepatitis-like findings, hemophagocytosis, and elevated serum ferritin and sIL-2R levels, she met the diagnostic criteria for HPS (5), leading to a confirmed diagnosis. In addition, the following symptoms met the diagnostic criteria for AOSD (6): persistent fever; elevated levels of WBCs, liver enzymes, and serum ferritin; splenomegaly and negativity for rheumatoid factor and antinuclear antibody; and exclusion of infections and malignancies. After admission, she was treated with 1 mg/kg prednisolone (PSL) and cyclosporine A, with a target trough level of 100-200 ng/mL. Although PSL was initially scheduled to taper every two weeks, increasing serum ferritin levels and thrombocytopenia reappeared on day 15, suggesting inadequate disease control. A treatment regimen of 5 mg/day of liposomal dexamethasone palmitate (DXS) for 3 days followed by 2.5 mg/day of DXS was added, which improved HPS so that DXS was gradually removed and discontinued (Fig. 3).

Figure 3.

The patient was treated for hemophagocytic syndrome (HPS) with 1 mg/kg of prednisolone (PSL) and cyclosporin A (CyA), targeting a trough concentration of 100-200 ng/mL. Although PSL was scheduled to be tapered every two weeks, HPS flared on Day 15, with rising serum ferritin levels and a decrease in platelet counts. Therefore, dexamethasone (DXS) was added while continuing to taper PSL, and DXS was gradually spaced out and eventually discontinued. On Day 43, new ground-glass opacities were observed via computed tomography (CT), leading to a diagnosis of alveolar proteinosis. Immunosuppressive therapy was tapered, but oxygenation continued to worsen. However, after tapering PSL to 17.5 mg or less, no further deterioration of pulmonary findings was noted. On Day 131, a second relapse of HPS was observed. Although the need for intensified immunosuppressive therapy was considered, the patient improved spontaneously without further immunosuppression. NC: nasal cannula

However, on Day 43, CT revealed ground-glass opacities and consolidations with a map-like distribution, predominantly in the bilateral lower lobes and dorsal aspects, which progressively worsened over time (Fig. 4). On Day 65, bronchoscopy revealed milky bronchoalveolar lavage fluid, and a transbronchial lung biopsy showed eosinophilic proteinaceous material filling the alveolar spaces (Fig. 2). Based on the chest CT results and histopathologic findings, which fulfilled the diagnostic criteria (4), the patient was diagnosed with PAP.

Figure 4.

Computed tomography (CT) on Day 43 revealed ground-glass opacities and consolidations, later diagnosed as pulmonary alveolar proteinosis (PAP), with milky bronchoalveolar lavage fluid and eosinophilic proteinaceous material filling the alveolar spaces on a transbronchial lung biopsy. Immunosuppressive drugs, particularly prednisolone (PSL), were thought to potentially worsen PAP and were carefully tapered while closely monitoring for a relapse of hemophagocytic syndrome. CT on Day 125 revealed progressive worsening of lung findings, with oxygenation deteriorating to the point of requiring 3 L/min via nasal cannula. Whole-lung lavage was considered in case of further worsening. However, after reducing PSL to 17.5 mg/day, no additional worsening was observed, and CT on Day 155 showed slight improvement in the lung findings. Subsequently, by Day 376, the abnormal findings on chest CT had resolved, and the glucocorticoid had been tapered to 10 mg of hydrocortisone.

Serum anti-GM-CSF antibody levels were below 0.3 U/mL, as measured by the Anti-GM-CSF ELISA Kit (MEDICAL & BIOLOGICAL LABORATORIES, Tokyo, Japan), and given the background of AOSD, the condition was classified as SPAP. While there were concerns about worsening PAP due to immunosuppressive therapy, discontinuation of these drugs could negatively affect the treatment and control of HPS. Therefore, we decided to taper the PSL to perform lung lavage if the pulmonary lesions worsened significantly.

Over the course of 3 months, the pulmonary findings worsened, and the oxygen requirement increased from 1 L/min via the nasal cannula to 3 L/min. However, after tapering PSL to 17.5 mg/day on Day 126, no further deterioration of the lungs was observed, and consequently, lung lavage was not required. On Day 131, an increase in serum ferritin levels and thrombocytopenia were observed. Although intensifying immunosuppression was considered, her condition improved spontaneously, and further treatment was not required. The patient underwent rehabilitation, received home oxygen therapy, and was discharged on Day 174. In the later course, by Day 376, the abnormal findings on chest CT had resolved, oxygen therapy was discontinued, and the GC dose was tapered to 10 mg hydrocortisone.

Discussion

We encountered a case of SPAP that developed during HPS treatment. PAP is characterized by the abnormal accumulation of surfactant in the alveoli, leading to hypoxemia and respiratory failure. PAP is etiologically classified into three distinct categories: APAP, caused by alveolar macrophages and neutrophil dysfunction caused by anti-GM-CSF antibodies; SPAP, caused by underlying diseases or conditions that reduce the number or function of alveolar macrophages; and congenital or hereditary PAP, caused by genetic mutations that affect surfactant production or clearance (7). The prevalence of PAP is rare, at 6.9 per million people, with APAP accounting for 92% of the cases, while SPAP is even rarer at 4% (8). The most frequent underlying condition of SPAP is the occurrence of hematologic diseases, particularly MDS (9). Although treatment of the underlying disease is recommended in cases of SPAP complicated by hematological diseases (10,11), therapeutic strategies for CTD/SPAP remain unclear. To investigate the association between CTD/SPAP and optimal treatment strategies, a literature review was conducted using PubMed, Google Scholar, and Web of Science databases with the following keywords: ‘secondary pulmonary alveolar proteinosis' and specific disease terms for various rheumatic conditions.

There were two cases of PAP associated with AOSD: one with APAP (12) and the other complicated by HPS with unknown anti-GM-CSF antibody status (13), as well as one case of PAP occurring during the course of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis complicated by HPS (14). However, there are no previous reports of SPAP associated with HPS complicated by AOSD. The scientific literature detailing the clinical course of CTD/SPAP is sparse, with only 12 reports describing 14 cases (Table). The most common type of CTD was Behçet's syndrome [6 cases (40%)], followed by idiopathic inflammatory myopathies [4 cases (27%)]. The median age at the CTD/SPAP onset was 49 years [interquartile range (IQR): 34-60] years old, occurring 3 (IQR: 1-12) years after the CTD onset. The clinical course of CTD was refractory or recurrent in 7 cases (47%), and CTD activity was low at SPAP onset in 10 patients (67%). CTD/SPAP treatment results were as follows: immunosuppressant withdrawal in 6 cases (40%) with 2 deaths due to infection and exacerbation of acute interstitial pneumonitis; lung lavage in 6 cases (40%) with no deaths; GM-CSF inhalation in 2 cases (13%) with no deaths; and no treatment in 2 cases (13%) with 1 death. Notably, 6 cases (40%) were initially misdiagnosed as worsening lung disease related to the primary CTD before being identified as SPAP, leading to increased immunosuppressive therapy, which was ineffective in all cases. These findings emphasize that, unlike treatment for MDS/SPAP, intensifying immunosuppressants for underlying disease does not always improve CTD/SPAP.

Table.

Clinical Characteristics and Outcomes of Secondary Alveolar Proteinosis Complicated by Autoimmune Diseases.

Case	Age at onset of CTD	Sex	Types of CTD	Treatment for CTD	Clinical course of CTD	Activity of CTD at the onset of PAP	Treatment for SPAP	Outcome	Ref
1	33	F	SLE/nocardiosis	PSL, IS (undescribed)	Undescribed	Undescribed	Tapering IS	Dead	［26］
2	21	F	SLE	PSL, MTX, MMF, LEF, BEL, RTX	Undescribed	Low	LL	Alive	［27］
3	70	F	ARS-ILD	PSL, CY, TAC	Refractory	Low	Tapering IS	Dead	［28］
4	28	M	CADM (MDA5)/pulmonary aspergillosis	PSL, ETN, RTX	Undescribed	Undescribed	Tapering IS	Alive	［29］
5	58	F	CADM (MDA5)	PSL, CY, CyA	Responsive	Low	Tapering IS	Alive	［30］
6	48	M	CADM (MDA5)	PSL, CY, TAC, TOF, MMF	Refractory	Low	Tapering IS	Alive	［31］
7	29	F	GPA	PSL, CY	Undescribed	Low	LL and GM-CSF	Alive	［32］
8	53	M	TAK	PSL, MTX, TCZ, CyA, TAC	Responsive	Low	LL	Alive	［33］
9	58	F	BS/MDS (trisomy 8 and 9, and GATA2)	PSL, colchicine, ADA, IFX, AZA	Refractory	High	LL and HSCT	Alive	［34］
10	37	F	BS/MDS(trisomy 8)/MAC	PSL, SSZ, CyA, IFX	Refractory	High	IS	Dead	［35］
11	27	M	BS/MDS(trisomy 8)/incasive aspergillosis	PSL, SSZ, AZA, ETN	Refractory	High	None	Dead	［35］
12	48	F	BS/MDS (trisomy 8)/MAC	Celecoxib	Responsive	Low	LL	Alive	［35］
13	45	M	BS	PSL, CyA	Responsive	Low	None	Alive	［36］
14	21	F	BS	PSL, SASP, colchicine	Refractory	Low	LL	Alive	［37］
15	74	F	Still’s disease/HPS	PSL, CyA	Refractory	High	Tapering IS	Alive	our case

ADA: adalimumab, AAV: anti-neutrophil cytoplasmic antibodies associated vasculitis, ANK: anakinra, AOSD: adult onset Still’s disease, APAP: autoimmune pulmonary alveolar proteinosis, ARS-ILD: anti-aminoacyl-tRNA synthetase antibody-positive interstitial lung disease, AZA: azatiopurin, BEL: belimumab, BS: Behçet’s syndrome, CADM: clinically amyopathic dermatomyositis, CTD: collagen tissue disease, CY: cyclophosphamide, CyA: cyclosporine A, ETN: etanercept, GPA: granulomatosis with polyangiitis, HPS: hemophagocytic syndrome, IFX: infliximab, IS: immunosuppressants, LEF: leflunomide, LL: lung lavage, MDS: myelodysplastic syndrome, MDA5: melanoma differentiation-associated gene 5, MMF: mycophenolate mofetil, MTX: methotrexate, PSL: prednisolone, RTX: rituximab, RUX: ruxolitinib, SASP: salazosulfapyridine, SSZ: sulfasalazine, TAC: tacrolimus, TAK: Takayasu arteritis, TCZ: tocilizumab, TOF: tofacitinib

Multiple factors may contribute to the development of CTD/SPAP. In a retrospective observational study of MDS/PAP (15), GCs were shown to be associated with disease progression, and the same was true in cases of APAP (16), although the presence of an underlying condition requiring GC treatment may have acted as a confounding factor. Given the evidence that GCs inhibit macrophage differentiation (17), they may contribute to the induction of CTD/SPAP. However, SPAP does not occur in all patients receiving intensive immunosuppressive therapy, suggesting that patient-specific factors contribute to its development. In addition to hematologic disorders and CTD, SPAP can be caused by infections, such as cytomegalovirus (18), Pneumocystis jirovecii (19), and non-tuberculous mycobacterial infections (20), as well as drug-induced SPAP related to immunosuppressive agents, including leflunomide (21), sirolimus (22), ruxolitinib (23), and mycophenolate mofetil (24). In our case, tocilizumab, administered once at a previous hospital, may also have been involved in SPAP, as previous reports have suggested an association between the use of biologics for systemic juvenile idiopathic arthritis and PAP (25). As these infections and drugs are often associated with hematologic disorders and CTD, identifying the exact cause of SPAP is frequently challenging. Therefore, the entity reported as CTD/SPAP is thought to encompass macrophage dysfunction due to excessive immunosuppression, abnormalities in CTD-specific immune mechanisms, or a combination of both. Regardless, in the treatment of CTD/SPAP, the activity of the underlying CTD is often low, and intensifying immunosuppression to improve the primary CTD is likely to be ineffective. This remains true even when CTD/SPAP is associated with infectious or drug-induced factors. Although some reports suggest that alveolar lavage is effective for CTD/SPAP, there may be a bias towards its application in patients with better overall condition. Given its high invasiveness, a comprehensive evaluation of respiratory symptoms and partial oxygen pressure is necessary prior to its implementation. In some cases, prioritizing the withdrawal of immunosuppressive therapy may be required.

In conclusion, when bilateral ground-glass opacities appear during the course of CTD, SPAP and withdrawal of immunosuppressive therapy should be considered. Treating the underlying disease does not necessarily lead to an improvement in SPAP.

Written informed consent was obtained from the patient for publication of this case report.

The authors state that they have no Conflict of Interest (COI).