Successful Whole-Lung Lavage in Anti–GM-CSF–Negative Pulmonary Alveolar Proteinosis: A Case Report

Introduction

Pulmonary alveolar proteinosis is a rare lung condition and was first described in 1958 by Rosen and colleagues [1–3]. The pathological hallmark of alveolar proteinosis is the excessive accumulation of lung surfactant in the alveoli due to impaired clearance by macrophages. The definition and management of this disease have evolved significantly over time, improving outcomes and reducing morbidity. Published reports have largely focused on autoimmune PAP or secondary PAP with identifiable causes, such as hematologic malignancies or occupational exposures. Several reports have demonstrated that PAP can mimic infectious pneumonia, frequently leading to delayed diagnosis and repeated courses of antibiotic therapy with only transient clinical improvement. However, cases in which autoimmune and secondary causes are systematically excluded but complete etiological classification remains challenging because of limited access to genetic testing are rarely reported. Moreover, data on the clinical course and management of such cases in routine clinical practice – particularly among older patients – remain limited, as most publications focus on diagnostic confirmation or therapeutic strategies rather than real-world diagnostic limitations and longitudinal clinical decision-making

In this report, we present a case of PAP initially misdiagnosed as recurrent pneumonia, with negative anti–GM-CSF antibodies and no identifiable secondary cause, in which hereditary PAP could not be definitively excluded due to diagnostic constraints. This case highlights common diagnostic pitfalls, practical challenges in PAP classification, and the clinical course following whole-lung lavage in a real-world clinical setting.

Case Report

PHYSICAL EXAMINATION:

Her vital signs at admission were blood pressure of 131/71 mmHg, heart rate of 78 beats/min, temperature of 36 °C, respiratory rate of 18 breaths/min, and an oxygen saturation of 93% on 3 L/min via nasal cannula. She had shallow but comfortable breathing. Lung auscultation revealed diffuse coarse crackles. No cyanosis, clubbing, or peripheral edema were observed. The remainder of the physical examination, including neurologic, cardiovascular, abdominal, musculoskeletal, lymphatic, and skin systems, was unremarkable.

DIAGNOSTIC STUDIES:

A complete blood count revealed white blood cell count was 8.6 G/L, hemoglobin was 125 g/L, hematocrit was 32%, and platelet count was 358 G/L. Her international normalized ratio (INR) and prothrombin time were within normal limits. Liver enzyme levels, creatinine level, electrolytes, C-reactive protein were normal. Arterial blood gas analysis, performed on 3 L/min via nasal cannula, revealed partial pressure of carbon dioxide (PCO2) of 32.4 mmHg, partial pressure of oxygen (PO2) of 61.4 mmHg, and bicarbonate (HCO3-) of 20.8 mmol. A chest X-ray demonstrated diffuse opacity in both lung fields (Figure 1A). A computed tomography (CT) scan revealed patchy areas of ground-glass opacity and widespread thickening of the intralobular and interlobular septa, which together create a “crazy paving” appearance (Figure 1B, 1C). Pro-BNP and the echocardiogram did not show evidence of acute heart failure. The next diagnostic procedure to be performed was bronchoscopy. The bronchial lumen was normal, with mild atrophy of the bronchial mucosa, and the BALF became progressively more opaque over time (Figure 2). BALF cellularity showed a predominance of lymphocytes, and a cytological examination was positive with PAS staining. The combination of the typical “crazy paving” pattern on CT and the milky BALF strongly suggested pulmonary alveolar proteinosis. The next step was to determine the underlying subtype. Anti–GM-CSF antibodies were negative, thereby excluding autoimmune PAP. A systematic evaluation for secondary causes of pulmonary alveolar proteinosis was performed in accordance with current guidelines. Microbiological investigations of BALF returned negative, including culture studies for bacteria, tuberculosis, and fungal infections. Clinical evaluation, complete blood count, and peripheral blood smear showed no abnormalities suggestive of an underlying hematologic disorder. Given the absence of abnormalities suggestive of hematologic malignancy, further invasive investigations such as bone marrow biopsy were not considered necessary. There was no history of occupational or environmental exposure, immunodeficiency, chronic infection, or use of immunosuppressive medications. In addition, there was no clinical or laboratory evidence of immune deficiency, chronic inflammatory disease, or chronic infections, including HIV, cytomegalovirus, or pneumocystis jirovecii. Genetic testing for hereditary PAP could not be performed due to the unavailability of specialized laboratory facilities; therefore, hereditary PAP could not be definitively ruled out.

CLINICAL COURSE:

She subsequently underwent 2 sequential WLL under general anesthesia to treat the right lung first, followed by the left 3 weeks later. The lavage fluid was opaque and had a characteristic milky appearance, developing a thick layer of sediment over time (Figure 3). The patient was discharged with home oxygen therapy, maintaining an oxygen saturation of greater than 94% with 3 L of oxygen/min for 2 months, and then gradually weaned off. After 6 months, she was asymptomatic, with a SpO2 of 96%, PaO2 76 mmHg while breathing room air. Eventually, radiological findings improved significantly (Figure 4).

Discussion

PAP is a rare respiratory disease characterized by alveolar accumulation of surfactants composed of proteins and lipids due to disruption of surfactant homeostasis that affects the production and clearance of surfactants. The main physiological consequence of PAP is impairment of gas exchange, which can lead to dyspnea, hypoxemia, or even respiratory failure [4]. While a clinical picture of slowly progressive nonspecific respiratory symptoms with typical radiological findings should suggest a diagnosis of PAP, BALF cytological analysis can confirm the diagnosis of PAP. Diagnosis of PAP relies on typical radiological features and bronchoalveolar lavage findings [3,5]. In most patients, a confirmatory biopsy is not necessary [2]. The choice of treatment depends on the etiology of PAP and the severity of symptoms. For patients with moderate to severe disease, WLL is still the first-line treatment of choice [2].

Surfactant is a complex mixture of lipids and proteins produced by alveolar type II epithelial cells [5]. Its primary functions are reducing surface tension and protecting against pathogens. Alveolar macrophages (AMs) are responsible for clearing excess surfactant from the alveolar spaces through phagocytosis and catabolism, a process regulated by granulocyte–macrophage colony-stimulating factor (GM-CSF) [6]. According to the underlying pathogenetic mechanisms, PAP is classified into 3 types: primary (including autoimmune and hereditary forms), secondary, and congenital. Primary PAP results from the disruption of GM-CSF signaling, leading to impaired surfactant clearance. In autoimmune PAP, the body produces autoantibodies against GM-CSF, which inhibits GM-CSF signaling, resulting in dysfunctional macrophages that are unable to effectively remove surfactant, leading to its buildup [4]. In hereditary PAP, mutations in genes encoding the GM-CSF receptor subunits result in conformational changes and reduced receptor function or cell surface expression. Secondary PAP occurs when other diseases lead to a reduction in the number and/or function of AMs [2,7]. In congenital forms, genetic mutations affect surfactant production or lung development [2]. Regardless of the type, these pathways lead to the same outcome: accumulation of surfactant in the alveoli, which impairs gas exchange and causes progressive respiratory symptoms.

Autoimmune PAP most commonly presents between the ages of 40 and 50, while hereditary and secondary forms may occur at different ages depending on the underlying etiology [8]. Most patients present with slowly increasing dyspnea on exertion and cough. Less commonly, they have fever, weight loss, or chest pain. Due to impaired alveolar macrophage function, PAP patients are at increased risk for opportunistic infections, particularly by nocardia, mycobacteria, and fungi [9]. Lung fibrosis occurs in up to 20% of cases, regardless of subtype, and generally develops in the late stages of the disease [10]. Clinical examination results are often normal and not specific. Cyanosis or digital clubbing may be present, and auscultation may reveal crackles. Older patients usually have the most severe form of PAP [2].

Chest radiography typically demonstrates symmetric, bilateral alveolar opacities, frequently in a “bat wing” distribution [2]. CT findings are highly suggestive of PAP and include ground-glass opacities, septal reticulations, and parenchymal consolidation, which together may create a “crazy paving” pattern. However, these findings are neither specific nor sensitive enough to establish a definitive diagnosis [2]. Crazy paving can also be observed in various lung conditions, such as acute respiratory distress syndrome, organizing pneumonia, acute interstitial pneumonia, and drug-induced pneumonitis. BALF characterized by a milky-opaque appearance is strongly suggestive of PAP [11]. BALF cellularity in PAP patients is often increased with a predominance of lymphocytes, and cytological examination of the BALF shows foamy macrophages which contain eosinophilic granules and amorphic material that stains PAS-positive [4]. Furthermore, BAL is crucial for ruling out pulmonary infections, which can complicate PAP of all forms. The subsequent evaluation focuses on determining the type of PAP, typically through serum GM-CSF autoantibody testing or genetic analysis [11].

Treatment strategies should be guided by the degree of impairment of lung function, CT imaging changes, blood oxygenation [2]. Whole-lung lavage (WLL) remains the gold standard therapy, even as pathogenesis-driven treatments like GM-CSF therapy, rituximab, and plasmapheresis emerge [11]. For patients with evidence of gas exchange impairment and either symptoms or functional impairment, bilateral WLL is recommended [12]. Since its first introduction in 1964, no standardized protocol for WLL has been established [13,14]. Briefly, WLL is performed under general anesthesia, and intubation is performed using a double-lumen endotracheal tube to ventilate one lung while washing the other with several liters of saline [12]. The interval between sequential WLL sessions and the selection of the initial lung to be treated differ among centers. Approximately half of centers perform the second lavage within 1 to 2 weeks of the first, while lung selection is either determined by radiological severity or, in other centers, routinely begins with the left lung due to its smaller volume [15]. Among autoimmune PAP, inhaled GM-CSF might be a promising therapeutic option. Because of its high levels of neutralizing GM-CSF autoantibodies, plasmapheresis to remove the autoantibodies and B-lymphocyte depletion using rituximab (an anti-B-cell monoclonal antibody) have been attempted [15]. In patients with PAP progressing despite WLL and pharmacological treatment, lung transplantation should be considered [16]. In secondary PAP, therapy should target the underlying conditions or the removal of the causative agent [11]. The clinical course of PAP is highly variable, ranging from spontaneous resolution to respiratory failure or infection [4]. Therefore, regular monitoring with symptom assessment, pulmonary function testing, and imaging is essential to guide appropriate management strategies.

This case highlights several clinically relevant aspects of pulmonary alveolar proteinosis (PAP) that are less frequently addressed in the literature, particularly diagnostic challenges, complexities in etiological classification, and the need for pragmatic clinical decision-making in routine practice. The initial diagnostic course in this patient reflects a common clinical challenge: the misinterpretation of PAP as recurrent or non-resolving pneumonia, particularly in older individuals with cardiovascular comorbidities. In our patient, advanced age and underlying coronary artery disease may have favored consideration of more common diagnoses, such as infectious pneumonia or heart failure-related pulmonary congestion, especially in the presence of nonspecific respiratory symptoms, intermittent low-grade fever, and overlapping radiological findings. The absence of sustained clinical improvement despite multiple courses of antibiotics should prompt reconsideration of alternative diagnoses. This case highlighted the importance of maintaining a broad differential diagnosis and considering PAP when infectious and cardiogenic causes fail to adequately explain the clinical course. The etiological workup in this patient demonstrates the practical relevance of a structured, guideline-based approach to the evaluation of secondary causes of PAP, particularly in older patients. Secondary PAP is most commonly associated with hematologic disorders resulting in impaired alveolar macrophage function. Importantly, hematologic malignancy-associated PAP is generally associated with a poor prognosis, with a reported median survival of approximately 16 months [2]. In our patient, evaluation for hematologic disorders, including myelodysplastic syndromes and chronic leukemias, revealed no abnormalities on clinical assessment, complete blood count, or peripheral blood smear. Furthermore, during 6 months of follow-up after whole-lung lavage, the patient remained clinically stable with radiological improvement, without features suggestive of an underlying progressive hematologic condition. Although longer observation is warranted, this short-term course is not suggestive of secondary PAP related to hematologic malignancy. Additional evaluation did not reveal evidence of immunodeficiency, chronic inflammatory disease, occupational or environmental exposure, or chronic or opportunistic infections. Despite this systematic evaluation, complete etiological classification could not be achieved because genetic testing for hereditary PAP was not available at our center. Although hereditary PAP is rare in adults, definitive exclusion requires molecular testing. This limitation reflects real-world diagnostic constraints and highlights the gap between guideline recommendations and clinical feasibility, underscoring the importance of transparent reporting rather than overclassification.

Given the negative anti–GM-CSF antibody result, WLL was instituted as the primary treatment without adjunctive exogenous GM-CSF or plasmapheresis. The optimal amount of fluid used for WLL remains debated. While there is general consensus regarding the single aliquot volume (approximately 800 mL of warm saline in adults), the total amount of saline infused per lung varies widely, from 5 to 40 L, with an average of 15.4 L per lung [15]. Higher volumes have been associated with more effective clearance of proteinaceous material, but also carry greater risks of fluid overload, hypoxemia, and procedure-related complications, particularly in older or comorbid patients [17,18]. In our patient, the right lung was lavaged first, guided by the greater severity of radiological involvement. A total of 5 L of saline was instilled, with 4.5 L retrieved as output. Three weeks later, the left lung was lavaged with a similar volume. A moderate lavage volume was deliberately chosen in view of the patient’s advanced age and pre-existing cardiovascular disease. This approach aligns with reports of favorable outcomes using reduced lavage volumes in high-risk patients, suggesting that a tailored strategy can be both effective and safer in selected populations [19]. Both recombinant GM-CSF therapy and plasmapheresis have been mainly applied in autoimmune PAP, where pathogenic neutralizing antibodies against GM-CSF are present. In negative anti-GM-CSF cases such as ours, there is little evidence supporting the efficacy of these approaches. Therefore, WLL alone was considered the most appropriate strategy. Ongoing clinical, functional, and radiological surveillance will be essential to evaluate the therapeutic response and to determine whether repeated lavage procedures are required.

In terms of clinical course, the patient’s outcome following whole-lung lavage was encouraging. She initially presented with respiratory failure requiring supplemental oxygen but showed marked improvement after the procedure, allowing discontinuation of oxygen therapy. At 6-month follow-up, she remained clinically stable with radiological improvement. Although a longer follow-up is warranted, this favorable short-term outcome supports the role of whole-lung lavage in appropriately selected patients and suggests the value of individualized management based on clinical severity rather than strict etiological categorization.

Conclusions

PAP is a rare but important differential diagnosis in patients with recurrent or non-resolving pneumonia. This case highlights the diagnostic challenges posed by its nonspecific clinical presentation and radiologic features that mimic other pulmonary conditions. Recognition of the characteristic “crazy paving” CT pattern and milky BAL fluid are key to timely diagnosis. WLL remains an effective therapeutic option with favorable outcomes. Clinicians should maintain a high index of suspicion for PAP in similar cases to avoid misdiagnosis and delayed treatment. A structured approach to exclude secondary causes, together with acknowledgment of real-world diagnostic limitations, is essential for classification and appropriate management. Whole-lung lavage was associated with favorable short-term clinical improvement, supporting individualized management in selected patients.