Myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis with silicosis, alveolar hemorrhage, and rapidly progressive glomerulonephritis: a case report

Introduction

Background

Dust generated during tunnel construction leads to occupational exposure to crystalline silicon dioxide (silica), causing a long-term lung disease called silicosis. Many complications like progressive systemic sclerosis, systemic lupus erythematosus, and Sjögren’s syndrome occur after silicosis (1). The underlying pathophysiology of these diseases involves autoantibodies such as anti-RNA polymerase, anti-topoisomerase (Scl-70; in progressive systemic sclerosis), anti-double-strain DNA, and anti-SM (systemic lupus erythematosus) antibodies.

Rationale and knowledge gap

Recently, another autoantibody, antineutrophil cytoplasmic antibody (ANCA), has been linked to diseases such as vasculitis, leading to the term ANCA-associated vasculitis (2,3). Research for the diagnosis and treatment of ANCA-associated vasculitis in clinical settings is still ongoing. Patients with silicosis have a 25-fold higher risk of ANCA-associated vasculitis than those without occupational diseases (1).

Objective

Herein, the author describes the case of a man who developed ANCA-associated vasculitis post-silicosis, resulting in severe alveolar hemorrhage and renal dysfunction. The case is presented in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-112/rc).

Case presentation

In April 1999, a Japanese man in his 50s presented with cough with sputum at Toyama Rosai Hospital. He worked as a tunnel digger for 33 years without appropriate respiratory protective equipment, exposing him to silica. He had a 28.5 pack-year smoking history, but he quit smoking at the age of 55. He also had hypertension and dyslipidemia. The records of treatment with propylthiouracil or a similar drug were unavailable. According to the patient, occult blood tests were positive since the age of 20. In March 1998, blood appeared in his sputum, and he underwent bronchoscopy at a core hospital, but no definitive diagnosis was made. Physical examination revealed no significant findings. Chest X-ray images upon arrival at the hospital revealed numerous small and large opacities of varying sizes, significantly in the right lung and the bilateral upper lung fields (Figure 1A). Non-contrast-enhanced computed tomography (CT) images showed numerous small opacities of varying sizes in the bilateral upper lung fields (Figure 1B,1C). Urinalysis at the first visit revealed protein positive or negative and occult blood 1+. The plain chest image findings and the patient’s history led to a diagnosis of silicosis. The plain chest image findings and the presence of sputum satisfied the requirements of the Pneumoconiosis Law of Japan. Therefore, the Ministry of Health, Labour, and Welfare confirmed that the patient suffered from an occupational illness due to his diagnosis of silicosis and associated secondary bronchitis and qualified him for compensation. Thereafter, the patient visited the outpatient department of my hospital once a month.

Figure 1 Chest images captured in 1999. (A) X-ray image of the plain chest. (B,C) Non-contrast-enhanced computed tomography images of the plain chest showing striations in the lungs and mediastinum in the upper thoracic region. Mediastinal lymphadenopathy with mild calcification is observed.

The patient underwent X-rays, other examinations (general chemistry blood tests, blood cell tests, general bacterial culture and identification test of sputum, antimicrobial culture and identification test of sputum, sputum cytology, respiratory function test, and arterial blood gas analysis), and urinalyses every 3–4 months. A urine test in November 2008 showed increased urinary protein and occult blood. Therefore, after consultation with a nephrologist, I measured the myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) levels, which were elevated at 15.9 U/mL (normal range, <9.0 U/mL). The patient was otherwise in good health, with no systemic or partial symptoms like fever, anorexia, weight loss, myalgia, or arthralgia, thus negating the presence of vasculitis. The chest radiograph captured at this point is shown in Figure 2. The attending physician and nephrologist recommended a renal biopsy owing to elevated MPO-ANCA levels, but the patient declined it because of invasiveness despite the absence of symptoms. Subsequent monitoring showed deteriorating urinary findings. In September 2009, he complained of systemic fatigue, fever, night sweats, bloody sputum, and difficulty breathing; therefore, he was admitted for detailed examination. He had no symptoms of viral infection or changes in the amount and characteristics of sputum before hospitalization. Physical findings at the time of admission were as follows: body temperature, 37.2 ℃; pulse, 64 bpm; blood pressure, 126/74 mmHg; percutaneous arterial oxygen saturation, 93%; and auscultation, indicating coarse crackles in the right dorsal region. The chest X-ray (Figure 3A) showed infiltration shadows in both lungs, although it was more prominent in the right lung. The CT image (Figure 3B) showed elevated lung field concentrations with unclear borders, primarily in the right central and lower lobes on the dorsal side. The biochemical tests results performed at the time of admission are presented in Table 1. The tests for hepatitis B, hepatitis C, and syphilis were negative. The progression of silicosis from 1999 to 2009, including radiographic findings, and the progression of hematuria and proteinuria are shown as a timeline in Figure 4.

Figure 2 Chest radiograph captured in November 2008.

Figure 3 Chest images captured in September 2009. (A) X-ray image of the plain chest. (B) Non-contrast-enhanced computed tomography image of the plain chest showing striations in the lungs.

Figure 4 Progression of silicosis from 1999 to 2009. OB, occult blood in urine; Prot., urine protein.

Based on physical findings and biochemical tests, respiratory infection was suspected; therefore, the patient was initially administered 1 g cefozopran hydrochloride twice daily. No improvement occurred; he was then administered 0.5 g meropenem trihydrate and 300 mg pazufloxacin mesylate twice daily, but with no improvement. MPO-ANCA levels were elevated to 690 U/mL; therefore, alveolar hemorrhage was suspected. Extensive periodic examinations ruled out diseases indicative from infiltrative shadows such as pulmonary edema, acute respiratory distress syndrome, drug-induced lung injury, bronchioloalveolar epithelial carcinoma, malignant lymphoma, sarcoidosis, and chronic eosinophilic pneumonia. Although bloody sputum is strongly suggestive of alveolar hemorrhage, the presence of bloody sputum is not a definitive diagnosis of alveolar hemorrhage. Therefore, to differentiate between the possible diagnosis of alveolar proteinosis or alveolar hemorrhage, bronchoalveolar lavage was performed in the bronchus of the right middle lobe; 50 mL of normal saline was injected thrice into the right middle lobe bronchus, and the fluid was recovered, which was found to be bloody with increasing redness. Subsequently recovered fluid showed higher concentrations of blood (Figure 5), and a diagnosis of diffuse pulmonary alveolar hemorrhage was confirmed. Bloody sputum resolved spontaneously. However, serum creatinine levels increased to 2.0 mg/dL after approximately 2 weeks, raising suspicion of rapidly progressive glomerulonephritis. The patient was transferred to a core hospital for further treatment. Renal tissue histopathology performed in October 2009 using hematoxylin and eosin staining (Figure 6) and Periodic acid-Schiff staining (Figure 7) showed cellular crescents in the glomeruli, and some glomeruli showed necrotic clotting, with interstitial inflammatory cell infiltration. Immunohistological staining did not show an accumulation of immunoglobulins and/or complement system components. Therefore, a diagnosis of necrotizing crescentic glomerulonephritis was made.

Figure 5 Bronchoalveolar lavage fluid collected in September 2009. The recovered bronchoalveolar lavage fluid is shown in order from left to right. The redness of the recovered fluid continuously increased.

Figure 6 Histopathology of renal tissue using hematoxylin and eosin staining. The image shows half-moon-shaped cellular formations in the glomerulus at 40× magnification.

Figure 7 Histopathology of renal tissue using Periodic acid-Schiff staining. (A) Magnification: 10×; (B) magnification: 40×.

Combination therapy with pulse methylprednisolone sodium succinate and cyclophosphamide led to remission. The patient was then followed-up at my outpatient clinic. Considering the disease course and biochemical test results, a diagnosis of silicosis with MPO-ANCA-associated vasculitis, associated alveolar hemorrhage, and rapidly progressive glomerulonephritis was established. Ultimately, the patient was prescribed 10 mg/day of prednisolone regularly, and his progress was observed.

In July 2011, the patient experienced a recurrence of bloody sputum, fever, and difficulty breathing, along with a body temperature of 38.1 ℃ and partial pressure of oxygen of 40.9 Torr, indicating advanced hypoxemia. CT imaging revealed lung field shadows with ground-glass opacity nearly covering the entire lungs and spread to the peripheral areas. Biochemical blood tests revealed elevated white blood cell counts and C-reactive protein, blood urea nitrogen, and creatinine levels. This confirmed a recurrence of MPO-ANCA-associated vasculitis; therefore, the patient was again transferred to the same core hospital and was treated with the same therapy, leading to remission again. The patient experienced two more recurrences before his death in November 2017; he was administered the same treatment during recurrences. The patient survived for 8 years and 1 month after diagnosis of MPO-ANCA-associated vasculitis, associated alveolar hemorrhage, and rapidly progressive glomerulonephritis, during which he experienced three recurrences.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The patient whose case has been described in the report is now deceased. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

Key findings

Herein, the author described the case of a man who developed ANCA-associated vasculitis after silicosis, leading to severe alveolar hemorrhage and necrotizing crescentic glomerulonephritis.

Strengths and limitations

The present case is the first case of survival for 8 years after confirming alveolar hemorrhage, and it was apparent that the patient’s death did not occur due to ANCA-associated vasculitis.

Comparison with similar researches

To the author’s knowledge and in the literature review, only three cases of ANCA-associated vasculitis after silicosis, complicated by alveolar hemorrhage and rapidly progressive glomerulonephritis, have been reported (4-6). Nakajima et al. (4) reported the case of a 63-year-old man with silicosis and elevated ANCA levels, complicated by alveolar hemorrhage and rapidly progressive glomerulonephritis. The patient died despite aggressive treatment using pulse and plasma exchange therapies (4). Vega Miranda et al. reported the case of a 34-year-old man with silicosis and glomerulonephritis due to ANCA-associated vasculitis. Alveolar hemorrhage was detected twice, and the patient died after starting cyclophosphamide, methylprednisolone, and intermittent renal dialysis co-treatment (5). Lee et al. reported the case of a 56-year-old man with silicosis, progressively deteriorating renal function, and shortness of breath. Chest imaging indicated ground-glass opacities. Because of the elevated ANCA levels, the patient was diagnosed with ANCA-associated crescent glomerulonephritis (6). This patient was treated with intravenous cyclophosphamide and prednisolone at 11.4 and 2 mg/kg/day, respectively, and underwent six plasma exchanges. The patient recovered; however, alveolar hemorrhage was not confirmed in this patient.

Explanations of findings

My patient had ANCA-related vasculitis, silicosis, and secondary bronchiolitis per Japanese pneumoconiosis law, increasing the risk of respiratory tract infections with common bacteria and tuberculosis. Another hospital, where the patient passed away, found the cause of the death to be bacterial pneumonia due to secondary bronchitis, that alongside silicosis, caused respiratory failure. Although the patient had recurrent ANCA-related vasculitis flare-ups, the direct cause of death was an adverse event from steroid administration, likely due to pulmonary infection with pathogens, possibly Staphylococcus aureus. Thus, steroid use, albeit with a small contribution, may have led to treatment-related death. However, in retrospect, steroids as maintenance therapy were successful. The patient demonstrated satisfactory progress. Elevated ANCA levels before disease onset and prompt diagnosis and treatment of alveolar hemorrhage likely contributed to a favorable outcome, including during recurrences. The bloody sputum in March 1998 may have been due to ANCA-associated vasculitis, with the patient experiencing five episodes of MPO-ANCA-associated vasculitis and alveolar hemorrhage.

ANCA was first reported in 1982 by Davies et al., who diagnosed a patient with focal necrotizing glomerulonephritis and detected IgG antibodies in his serum by staining human neutrophils (7). Subsequent research identified two types of ANCA-associated vasculitis: PR3- and MPO-ANCA-associated vasculitis. ANCA-associated vasculitis is an autoimmune disease characterized by small-vessel vasculitis throughout the body, particularly in the kidneys and lungs, with ANCA present in the blood plasma (2).

Unlike in Europe and the US, Japan reports many cases of microscopic polyangiitis (MPA), often MPO-ANCA positive (8). Therefore, Japan has specific clinical guidelines for ANCA-associated vasculitis (9). Applying these guidelines to my patient (ANCA positive or anti-myeloperoxidase-ANCA positivity, pauci-immune glomerulonephritis, rapidly progressive glomerulonephritis, and alveolar hemorrhage) confirms MPA.

A previous genetic study shows approximately 50% of Japanese MPA patients test positive for HLADRB1*0901, with significantly higher expression than in healthy individuals (10). In the present case, human leukocyte antigen testing was not performed. Infections are suggested as potential triggers for ANCA-associated vasculitis (11), but my patient tested negative for syphilis, hepatitis B, and hepatitis C, with no viral infection symptoms or sputum abnormalities, making infection an unlikely cause. Drug-induced ANCA-associated vasculitis, linked to propylthiouracil and hydralazine (12,13), was also ruled out as my patient did not consume these drugs.

Furthermore, the correlation between current smoking and MPO-ANCA-positive diseases is suggested to be stronger than that between former smoking and MPO-ANCA-positive diseases (14). The findings of a recent review suggest that smoking affects the prevalence, clinical characteristics, and prognosis of ANCA-associated vasculitis (15). Since the patient was an ex-smoker, the influence of smoking cannot be ruled out. Tervaert et al. reported a significant correlation between silica exposure and ANCA-associated vasculitis with MPO-ANCA positivity (16). Hogan et al. reported that activities and environments in which there was exposure to silica dust in low concentrations were much more strongly correlated to ANCA-related small vessel vasculitis than the actual onset of silicosis (17). The patient had long-term occupational silica exposure, potentially contributing to ANCA-associated vasculitis.

Additionally, the proximity of local quarries to residential neighborhoods affects the prevalence of ANCA-associated vasculitis (18). Gregorini et al. reported that 43.5% of ANCA-positive hospitalized patients and 3.1% of patients with other kidney diseases had a history of occupational exposure to silica dust and that MPO-ANCA caused the disease in which necrotizing crescentic glomerulonephritis was presented (19).

Moreover, two reports have suggested that the number of patients with ANCA-associated vasculitis increased after an earthquake (20,21). Yashiro et al. reported that after the 1995 Hanshin-Awaji Earthquake, the incidence of MPO-ANCA-associated vasculitis in the affected regions increased compared with other regions, possibly due to a significant increase in the amount of silica in the atmosphere (20). Takeuchi et al. reported that after the 2011 Great East Japan Earthquake, the number of MPA cases increased in the affected region (21). They also reported more advanced symptoms and a higher mortality rate among patients in the group in which disease onset occurred after the earthquake than among those in the group in which disease onset occurred before the earthquake. They attributed this to the tsunami wave that occurred after the earthquake because it carried sludge containing a high amount of silica onto the land. However, I propose that the people were also affected by silica that originated from buildings destroyed by the tsunami.

The lungs of the patient in the present report had previously been exposed to large amounts of silica dust, which caused silicosis. The initially observed alveolar hemorrhage and rapidly progressive glomerulonephritis subsided temporarily and then recurred. Therefore, the patient experienced at least two episodes of onset and worsening of vasculitis. However, it is unclear whether the vasculitis was the direct cause of other conditions.

Implications and actions needed

Considering the case in the present report and previous studies, the onset of ANCA-associated vasculitis is thought to be due to environmental exposure and genetic factors. However, the worsening of the disease may be triggered by some other factor(s).

Conclusions

In conclusion, for patients with silicosis, accompanied by bloody sputum or other symptoms, ANCA-associated vasculitis, besides tuberculosis and lung cancer, should be considered. Additionally, it is necessary to pay close attention to the possible onset of rapidly progressive glomerulonephritis because it is sometimes fatal. In addition, when examining a patient with rapidly progressive glomerulonephritis, attention must be paid to whether the patient has had previous exposure to silica dust, regardless of whether or not the exposure was occupational. Because such exposure can lead to more severe diseases, there is a need to approach such cases with great care. There remains a need to gather more detailed data on many patients to better understand the pathology of this disease.

Acknowledgments

The author thanks Editage, Cactus Communications, for providing editorial support in the form of medical writing, assembling tables, creating high-resolution images based on author’s detailed directions, collating author comments, copyediting, fact checking, and referencing.

Funding: None.

Footnote

Reporting Checklist: The author has completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-112/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-112/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-112/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The patient whose case has been described in the report is now deceased. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made. Despite the author’s rigorous efforts, the author could not contact the deceased's family to obtain their consent to publish the case report. The paper has been sufficiently anonymized not to cause harm to the patient’s family.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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