Autoimmune Pulmonary Alveolar Proteinosis That Improved after a COVID-19 Episode

Abstract

Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction owing to the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. A 77-year-old man with APAP was referred to our hospital for whole-lung lavage (WLL) due to oxygenation exacerbation and pulmonary shadows. The patient had had coronavirus disease 2019 (COVID-19) during the APAP evaluation before WLL. About three months after COVID-19 resolved, his oxygenation and shadow reflecting APAP had obviously improved, thus avoiding the need for WLL. We suspected that the improvement in APAP was due to various immunological reactions induced by COVID-19.

Introduction

Pulmonary alveolar proteinosis (PAP) is characterized by phospholipid and surfactant protein accumulation in the alveolar spaces owing to defective surfactant clearance by alveolar macrophages (1). Autoimmune PAP (APAP), which accounts for the largest proportion of PAP cases (2,3), is caused by macrophage dysfunction due to neutralizing antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) (4). Anti-GM-CSF antibodies prevent terminal differentiation of alveolar macrophages, thus impairing surfactant catabolism in the lung (4). Patients with APAP are more susceptible to infections than healthy individuals because of macrophage and neutrophil dysfunction (5).

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hyperactivation of the immune system with the release of inflammatory cytokines, including GM-CSF, contributes to lung injury in patients with COVID-19 (6-9).

Papiris et al. reported a multicenter European retrospective study of patients with PAP and COVID-19, in which patients with PAP experienced similar rates of COVID-19 as the general population and high rates of hospitalizations and deaths, underscoring the vulnerability of this population and the need for preventive measures to avoid infection (10). Although GM-CSF signaling is suppressed in APAP and overexpressed in COVID-19, the effect of SARS-CoV-2 infection on the clinical course of APAP remains unclear.

We herein report a case of APAP that improved after a COVID-19 episode. Our findings suggest the involvement of various immunological interactions between the two diseases, including the GM-CSF-mediated cascade.

Case Report

A 77-year-old man was referred to our hospital for a close examination of an abnormal pulmonary shadow on computed tomography (CT) for follow-up after surgery for renal cell carcinoma. He had a 17-pack-year smoking history but no coexisting pulmonary disease. He had worked in the construction industry and had a history of minor exposure to asbestos. Chest CT showed widespread bilateral diffuse ground-glass opacities with superimposed intra- and interlobar septal thickening in the bilateral lower lobes, generally referred to as a “crazy-paving” pattern.

He underwent bronchoscopy, and the bronchoalveolar lavage fluid showed a milky appearance, with a microscopic examination revealing granular eosinophilic material with many foamy macrophages. Transbronchial lung biopsy specimens demonstrated peripheral air spaces filled with granular eosinophilic amorphous material. The material stained positively for periodic acid-Schiff and surfactant protein (SP)-A, consistent with the diagnosis of PAP. His serum anti-GM-CSF antibody level was high at 45.9 μg/mL [this anti-GM-CSF antibody level was measured by a specific enzyme-linked immunosorbent assay previously reported; normal range: <3.33 μg/mL (11)]. Therefore, the patient was diagnosed with APAP.

His respiratory distress worsened with exertion, and his modified Medical Research Council dyspnea scale (mMRC) (12) deteriorated from grade 0 to grade 2. His percutaneous oxygen saturation (SpO₂) during exercise was below 88%, and he received home oxygen therapy for respiratory failure. The serum levels of Krebs von den Lungen 6 (KL-6), SP-D, SP-A, carcinoembryonic antigen (CEA), and cytokeratin 19 fragment (CYFRA), previously reported as biomarkers for PAP (2,13), continued to increase. The pulmonary shadows on CT gradually expanded. We assessed him as having APAP deterioration and considered performing whole-lung lavage (WLL).

However, a cough and fever (37.9°C) developed 1.5 years after the APAP diagnosis, immediately after planning to perform WLL. The SARS-CoV-2 antigen was detected in a nasal swab sample, and the patient was diagnosed with COVID-19. He had been vaccinated twice for COVID-19 at that point. However, he had not been vaccinated for several months since his second vaccination. Several days after the COVID-19 diagnosis, his SpO₂ level decreased to approximately 90% at rest, and blood tests showed an elevated C-reactive protein (CRP) level of 6.55 mg/dL. No changes were detected in the pulmonary shadows on radiographs during the COVID-19 episode. The patient was treated with remdesivir, an antiviral drug, but without steroids. His pulmonary symptoms resolved, and his CRP levels normalized within one week of the COVID-19 diagnosis.

After the COVID-19 episode, the patient's oxygenation improved, and WLL was not needed. Serum KL-6, which was 16,123 U/mL at the time of the COVID-19 diagnosis, decreased to 6,373 U/mL at 3 months later. Levels of other biomarkers, such as CEA, CYFRA, SP-A, and SP-D, also began to decrease after COVID-19. The SP-A and SP-D transitions were not as obvious as those of KL-6, CEA, and CYFRA (not shown in Figure). We confirmed that the abnormal pulmonary shadows on CT had remarkably disappeared three months after the COVID-19 diagnosis (Figure). Pulmonary function tests showed that the forced vital capacity (FVC), vital capacity (VC), and diffusing capacity for carbon monoxide (DLco) values, which had been deteriorating before COVID-19, had improved after COVID-19 (Table 1). The patient’s clinical course suggested that APAP had improved after the COVID-19 episode.

Figure.

Clinical course. COVID-19: coronavirus disease 2019, mMRC: modified Medical Research Council dyspnea scale, HRCT: high-resolution computed tomography, KL-6: Krebs von den Lungen-6, CEA: carcinoembryonic antigen, CYFRA: cytokeratin 19 fragment, CRP: C-reactive protein. Desaturation on exertion: percutaneous oxygen saturation (SpO₂) below 90% during exercise. Desaturation at rest: SpO₂ at rest is <90%. All days are counted from the diagnosis of COVID-19.

Table 1.

Pulmonary Function Test Results before and after the COVID-19 Episode.

		Number of days from the diagnosis of COVID-19, days
		-626		-11		87
FVC, L (%pred)		2.03 (62.2%)		1.31 (43.8%)		1.51 (50.3%)
VC, L (%pred)		2.02 (62.2%)		1.32 (44.1%)		1.45 (48.3%)
DLco, mL/min/mmHg (%pred)		12.68 (98.7%)		8.57 (72.6%)		9.95 (87.3%)
DLco/VA, mL/min/mmHg/L (%pred)		3.98 (93.0%)		3.48 (82.3%)		3.83 (90.5%)

FVC: forced vital capacity, VC: vital capacity, DLco: diffusing capacity for carbon monoxide, DLco/VA: diffusing capacity for carbon monoxide/alveolar volume, %pred: percentage of measured to predicted values. Both days were recorded during the COVID-19 diagnosis.

Discussion

In the present case, the respiratory status, biomarkers of APAP, and pulmonary shadows, which had gradually worsened before the COVID-19 diagnosis, improved after the COVID-19 episode.

To our knowledge, this is the first case report of APAP remission after COVID-19. Three cases of APAP complicated by viral infections other than the present case have been reported (Table 2). We previously reported a patient with APAP whose disease severity remitted after an episode of herpes encephalitis (15). Two cases of APAP complicated by viral pneumonia have been reported (14,16). In both cases, the pulmonary condition worsened immediately after infection with H1N1 influenza; however, there were no details on the clinical course of APAP after infection.

Table 2.

Characteristics of Reported Cases of Concomitant APAP and Viral Infection.

	Case number
	1	2	3	4
Reference/year	(14)/2011	(15)/2017	(16)/2019	Our case/2023
Country	Italy	Japan	Saudi Arabia	Japan
Age, sex	41, female	40, female	38, female	77, male
Infection	H1N1 influenza pneumonia	Herpes encephalitis	H1N1 influenza pneumonia	COVID-19
Treatment of infection	Antibiotics, steroid, oseltamivir	Antiviral treatment	Antibiotics, oseltamivir	Remdesivir
Clinical course after infection	Pulmonary condition worsened and a lobar lavage was performed	Improvement of encephalitis and subsequent remission of APAP	Temporary worsening of pulmonary condition immediately after infection	Temporary worsening of pulmonary condition immediately after infection and subsequent remission of APAP

APAP: autoimmune pulmonary alveolar proteinosis

The clinical course of APAP has been reported to be altered after infection (15,17), although APAP spontaneously resolves at a certain rate (7.9-30%) (2,18). In reports in which APAP improved after an infectious disease (15,17,19-23), it was not conclusive whether the improvements were due to the infection or its treatment. Intriguingly, certain bacterial and viral infections have been shown to elevate serum GM-CSF levels (24), implying an association between GM-CSF and the improvement of APAP condition.

In COVID-19, an excessive and uncontrolled host immune response contributes to lung injury more than the toxicity of SARS-CoV-2 itself (6,7). Serum levels of various inflammatory cytokines, including GM-CSF, tend to be higher in patients with COVID-19 than in healthy controls and are correlated with disease severity (9,25). GM-CSF enhances the production of various inflammatory cytokines (26) and is a key component of the hyperinflammatory response in COVID-19 (8,27,28). A monoclonal antibody against GM-CSF is a candidate for treating COVID-19, and a randomized controlled trial has been conducted with no conclusive results (29).

These results led to the hypothesis that changes in the cytokine profile due to COVID-19, including elevated GM-CSF levels, affect the terminal differentiation of alveolar macrophages and trigger APAP improvement. It has also been reported that SARS-CoV-2 infects alveolar macrophages directly via the S-protein-angiotensin-converting enzyme 2 interaction and alters their cytokine profiles (30); the improvement of APAP in our case may also involve this mechanism. Although COVID-19 was not severe in this case, we speculate that a certain degree of hyperinflammatory response with the production of various cytokines occurred, considering the markedly elevated CRP levels. Because of the complicated immunological interaction between APAP and COVID-19, it is speculated that there are many other mechanisms involved besides those mentioned above. In this case, the possibility of spontaneous improvement cannot be ruled out. However, given the trend in the clinical course after COVID-19, we suspect that COVID-19 contributed to the alteration of the clinical course of APAP. The triggers for spontaneous APAP resolution remain unknown. Given the course of this case, it is hypothesized that a certain number of cases thought to have spontaneous resolution may have been triggered by subclinical or mild infections.

This case had several other inconclusive findings. First, oxygenation temporarily worsened immediately after the COVID-19 diagnosis (Figure). Since APAP does not usually cause acute deterioration, we suspect that this temporary worsening of respiratory status was due not to APAP exacerbation but to COVID-19. Second, among the disease markers of APAP, both CYFRA and CEA slightly decreased from Day -12 to Day 0, as shown in Figure. There is a possibility that APAP may have spontaneously resolved immediately before COVID-19, but we consider this possibility to be low. KL-6, the most representative disease marker of APAP (2,13), slightly increased from Day -12 to Day 0. The values of these blood tests fluctuate within a certain range, and it is impossible to determine whether the disease has improved or worsened at a single point. Third, respiratory function tests (Table 1) showed low VC and FVC values compared to DLco. This pattern is observed in some pleuroparenchymal fibroelastosis (PPFE) cases (31); however, there was no evidence of interstitial pneumonia in the lung fields, including PPFE, on chest CT. The patient had a history of asbestos exposure, but no pleural lesions were observed on chest CT. We were unable to determine the cause of this abnormality. Fourth, the impact of remdesivir and vaccination on APAP is unknown. A case report of concomitant APAP and H1N1 influenza infection indicated that antiviral therapy with oseltamivir seemed to ameliorate APAP (16). Although we were unable to find any studies that mentioned the relationship between remdesivir and APAP, GM-CSF, or macrophage, the influence of remdesivir on the clinical course of APAP in our case cannot be completely ruled out. The patient had been vaccinated twice for COVID-19 but had not received any vaccination for several months before contracting COVID-19. There have been several reports of exacerbations of interstitial pneumonia after messenger RNA COVID-19 vaccination (32,33), suggesting that immune cells may be activated by vaccination. Therefore, it cannot be ruled out that the vaccination may have affected the clinical course of APAP. However, considering the blank time between vaccination and APAP improvement in this case, it is highly unlikely that vaccination would have ameliorated APAP.

Although some cases of APAP remission are triggered by infection, as in our case, 20% of deaths in patients with APAP are due to secondary infections (18). Although new therapeutic approaches for APAP, such as GM-CSF inhalation (34,35), are now being developed, its treatment remains difficult because of the unpredictable and complex clinical course of this disease, which can be altered by infection. Larger-scale studies are warranted to determine the relationship between the prognosis of patients with APAP and infectious diseases. These studies may lead to the development of novel treatments for APAP.

Conclusion

This is the first case report of marked improvement in APAP after a COVID-19 episode. This case suggests that the immunological response to the SARS-CoV-2 infection affects the clinical course of APAP.

Written informed consent for publication was obtained from the patient described in this article.

Author's disclosure of potential Conflicts of Interest (COI).

Yoshikazu Inoue: Advisory role, SAVARA.