FormalPara Key Summary Points

Post-COVID-19 pulmonary sequelae and pulmonary alveolar proteinosis can have comparable symptoms and radiographic features and may not be easily distinguishable. High suspicion index is required to diagnose proteinosis, particularly in long COVID-19 cases non-responsive to corticosteroid treatment.

COVID-19 can be a potential trigger for the development of PAP, although this association remains poorly understood.

Whole lung lavage (WLL) is the primary treatment for PAP. It is essential to consider a patient’s position when determining the optimal lung lavage approach. Corticosteroid therapy can exacerbate proteinosis.

Introduction

Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by the accumulation of surfactant protein in the alveoli, leading to disturbances in gas exchange and ultimately respiratory failure. The pathophysiology of PAP involves either increased production or impaired clearance of surfactant, with the latter pathway more prevalent [1]. PAP is a rather rare disease. In Japan and the United States, where the largest population studies on PAP have been carried out, the estimated prevalence is around 6.2 per million and 6.87 per million, respectively [2, 3]. Patients with PAP usually present with non-specific clinical manifestations, including dyspnea (39%), chronic cough (21%), fatigue, chest discomfort, and weight loss [1]. Chest high-resolution computed tomography (HRCT) scan typically shows ground-glass opacities (GGO) and interlobular septal thickening, which is termed crazy-paving pattern. Its diagnosis requires a high suspicion index combining radiological characteristics and milky appearance of bronchial lavage fluid (BLF) [4]. After contracting COVID-19, many convalescent patients still experienced lingering symptoms. The persistent respiratory symptoms and imaging abnormalities are comparable to those in many interstitial lung diseases (ILD), including PAP, and therefore a keen observation is necessary for their identification [5]. We report herein a case of PAP initially misdiagnosed as post-COVID-19 pulmonary sequelae.

Case Report

A 44-year-old non-smoker male patient with unremarkable past history presented to the outpatient long COVID-19 clinic reporting progressive exertional dyspnea, dry cough, fatigue, and 5-kg weight loss for 3 months. He had been fully vaccinated with a booster shot. Four months earlier, he had a mild case of COVID-19 and was treated with Molnupiravir, from which he recovered in 2 weeks. One month after infection, he began to experience exertional dyspnea and occasional dry cough. Clinical examination at that time point revealed normal vital signs except a mild peripheral oxygen desaturation (SpO2 at 93% on room air). His body mass index was 23.9 kg/m2. Chest X-ray (CXR) demonstrated bilateral diffuse alveolar opacities predominantly in the basal and perihilar regions (Fig. 1A). Spirometry showed a low forced vital capacity of 2.50 L (65% predicted) and a forced expiratory volume in one second of 2.32 L (76% predicted). The patient was diagnosed with post-COVID-19 pulmonary sequelae and treated with oral methylprednisolone 16 mg per day.

Fig. 1
figure 1

Chest X-rays (CXR) showed opacities in bilateral lower lung zones. A CXR at the outpatient long Covid-19 clinic. B CXR undertaken 3 months later

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After 3 months of corticosteroid treatment, he showed no improvement and was referred to our hospital. On the physical examination, the patient presented normal vital signs, but SpO2 was only 90% on room air. Chest auscultation revealed bilateral fine crackles on inspiration at the lower lung zones. Cell blood count revealed leukocytosis (white blood cells [WBC] 16.08 G/L), with 78.8% neutrophils and 15.1% lymphocytes. Liver enzymes and kidney function were normal. The serum levels of C-reactive protein, procalcitonin, and lactate dehydrogenase were 28 mg/L (normal value < 6 mg/L), 0.18 ng/mL (normal value < 0.05 ng/mL), and 628 U/L (normal value 120–246 U/L), respectively. Autoantibody tests, including antinuclear antibody, anti-double-stranded DNA, rheumatoid factor, and anti-cyclic citrullinated peptide, were negative. The second CXR showed an increase in pulmonary opacities (Fig. 1B). The following chest HRCT presented crazy-paving pattern with GGOs superimposed with thickened reticular lines in both lung fields, predominantly on the left lung, with the presence of sharply demarcated areas of lobular sparing (Fig. 2A). Fibreoptic bronchoscopy showed normal mucosa but a milky appearance of BLF. Periodic acid-Schiff (PAS) staining was positive, confirming a large amount of proteinaceous material in BLF. Tests for Mycobacterium tuberculosis, bacterial, and fungal cultures were all negative. Diagnosis of PAP was established, and lung lavage was indicated. Figure 3 illustrates the outline of the disease timeline.

Fig. 2
figure 2

Chest computed tomography (CT) before and after conducting whole lung lavage. A The pre-lavage chest CT demonstrated a widespread diffuse ground-glass pattern. B The post-lavage CT showed reduction in opacities on the left lung but little change in mediastinal lung zones (red arrows)

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Fig. 3
figure 3

The outline of symptomatic, diagnostic, and therapeutic timelines for this reported case

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The patient, placed in the left lateral decubitus position, was intubated with a double-lumen endotracheal tube. A bronchoscopy was performed afterward to check that the ends of the endobronchial tube were placed in the correct positions (right and left main bronchus). After a short period of preoxygenation with fraction of inspired oxygen (FiO2) 100%, 1 L of saline 0.9% was instilled into the left lung and the end-tube was clamped afterward. A respiratory physiotherapist then performed tapotement and vibration for 5 min to enhance the clearance of proteinaceous secretion before discharging saline. The colour of the lavage fluid turned from an opaque to a clearer appearance after infusion and drainage cycles (Fig. 4). An approximate total of 15 L of 37 °C saline 0.9% was used. At the end of the procedure, any residual water was aspirated, and the lung was re-ventilated with FiO2 100%. The patient was then transferred to the recovery unit and extubated on the same day. In the following days, the patient was clinically stable, with SpO2 increasing to 96% at room air. Follow-up chest HRCT showed a reduction in lung opacities but the mediastinal left lung zone had the least improvement (Fig. 2B). At follow-up to the present, he has been healthy and returned to his daily work. Chest HRCT undertaken 4 months after lung lavage showed the stable opacities in the right lung. Written informed consent was obtained from the patient for the publication of data and figures included in this article.

Fig. 4
figure 4

The appearance of bronchoalveolar lavage changes from opaque to clear after lung lavage cycles

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Discussion

A subset of post-COVID-19 patients still experiences prolonged respiratory symptoms. In a recent meta-analysis of 54 studies and two medical record databases including 1.2 million symptomatic SARS-CoV-2 individuals across 22 countries, an estimated 3.7% of total patients reported having ongoing respiratory problems [6]. This is true even for patients with mild COVID-19 who did not require hospitalization. In a longitudinal study, at 5 months after infection, 55% of patients exhibited symptoms consistent with post-COVID-19 sequelae [7]. As for radiographic findings, long-term pulmonary abnormalities can persist for up to 1 year [8]. The most prevalent findings are GGOs, parenchymal bands, and reticular patterns. The comparable clinical and radiographic characteristics of post-COVID-19 pulmonary sequelae with those of PAP and other ILD can be a red herring, masking the real diagnosis. Indeed, radiographic differences between COVID-19 and PAP do exist, but they require careful observation to identify and may not always be easily distinguishable. GGOs in COVID-19 tend to be distributed peripherally, while opacities with perihilar prominence are seen in proteinosis, with the juxtaposition of damaged lobules and normal secondary lobules [9]. In our case, the patient was initially diagnosed with long COVID-19 syndrome and treated with oral corticosteroid for 3 months without significant improvement. We suspected another cause, indicated fibreoptic bronchoscopy, and confirmed the diagnosis of PAP.

PAP is an interstitial lung disease characterized by the accumulation of surfactant in alveolar spaces. The surfactant is composed of proteinaceous material that has high lipid content and is positive with PAS stain. PAP can be divided into three types: autoimmune, congenital, and secondary. Ninety percent of PAP cases are classified as idiopathic or autoimmune [2], which is the result of autoantibodies neutralizing granulocyte–macrophage–colony-stimulating factor (GM-CSF). Surfactant clearance by alveolar macrophage is impaired when the GM-CSF signalling is disrupted. Congenital PAP is characterized by genetic malfunctions in surfactant production and is often detected in newborns. Secondary PAP results from dust inhalation, infection, immunosuppression, and hematologic disorders causing alveolar macrophage dysfunction. In our case, PAP developed 1 month after COVID-19 infection, suggesting the possible causal relationship between COVID-19 infection and PAP. As PAP has been documented to develop after other viral infections (Epstein–Barr virus, cytomegalovirus, parainfluenza virus, and human immunodeficiency virus) [10,11,12,13], the plausible hypothesis that COVID-19 plays a causative role in proteinosis development might be promising. The pathogenic mechanisms could be the generation of an inhibitory autoantibody to GM-CSF [14] or the impairment of alveolar macrophage after COVID-19 infection. SARS-CoV-2 can replicate inside alveolar macrophages, alter their normal function, and drive them into a pro-inflammatory state [15]. Tissue-resident alveolar macrophages can be diminished in number, even after a mild case of COVID-19 [16]. On the other hand, this patient could have had pre-existing PAP, and COVID-19 infection and corticosteroid treatment resulted in the flare-up.

Corticosteroids can affect the onset and progression of PAP. As the patient was initially identified with post-COVID-19 syndrome, he was given corticosteroid therapy for an extended period. Published evidence has demonstrated improvement in radiographic patterns and lung function with systemic corticosteroids in post-COVID-19 patients with persistent parenchymal abnormalities, probably due to the corticosteroid effect on treating the organizing pneumonia component [17]. However, immunosuppression can lead to clinical deterioration in PAP. In a cohort study including 31 patients with autoimmune PAP prescribed glucocorticoid, 23 cases (74.1%) had worsened disease severity [18]. Although the exact mechanism for worsening disease is unknown, it is likely that corticosteroids inhibit GM-CSF production [19]. This further emphasizes the importance of timely diagnosis of PAP in post-COVID-19 patients.

Whole lung lavage (WLL) is still the hallmark treatment for PAP. The procedure is performed under general anaesthesia. Lipoproteinaceous material and anti-GM-CSF antibodies can be removed by continuous cycles of instilling and discharging saline 0.9% in one side of the lung while another side is fully ventilated. In our case, the left lung was washed first since it was more severely impacted on the chest HRCT. Due to the rarity of the condition, there are no specific instructions for performing the WLL technique, especially in choosing the most appropriate position in which to conduct the procedure. Our case showed modest improvement in the mediastinal left lung zone, which can be attributed to the left decubitus position and the influence of gravity in diminishing the effectiveness of the lavage procedure in this zone. All these factors should be taken into consideration when establishing the optimal position for lung lavage.

Conclusion

PAP is a rare lung condition and may occur after a COVID-19 infection. Distinguishing between PAP and post-COVID-19 pulmonary sequelae can be challenging, but a high level of suspicion can help prevent a misdiagnosis.