The successful treatment of microscopic polyangiitis associated with non-tuberculous mycobacterial-pulmonary disease

Abstract

While the incidence and prevalence of non-tuberculous mycobacterial-pulmonary disease (NTM-PD) are increasing and microscopic polyangiitis (MPA) is common in East Asian countries, case reports of MPA associated with NTM-PD are limited. A 72-year-old male receiving treatment for NTM-PD with antibiotics was referred to our hospital with fever and arthralgia that developed a few months previously. A blood test revealed the presence of the myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) and renal impairment. Based on a pathological examination of renal tissue, which showed crescentic glomerulonephritis, the patient was diagnosed with MPA. Due to acute kidney injury and strongly positive MPO-ANCA, pulse steroid therapy was initiated followed by intravenous rituximab (RTX). The patient also received plasmapheresis (14 sessions). Renal dysfunction was reversed. MPA associated with NTM-PD is extremely rare and, thus, there is currently no established treatment. Our patient was diagnosed with MPA based on the findings of renal biopsy while receiving treatment for NTM-PD. RTX and plasmapheresis combined with systemic glucocorticoid therapy were initiated before these clinical conditions had fully recovered. Although MPA secondary to NTM-PD may be more refractory to treatment than primary MPA in the presence of a very low interferon-gamma (IFN-γ) level, this case was successfully treated with steroids, RTX, and plasmapheresis.

Introduction

Non-tuberculous mycobacteria (NTM) species are mycobacterial species other than those belonging to the Mycobacterium tuberculosis complex and M. leprae. Mycobacterium avium complex (MAC) is one of most common causes of NTM-PD. The incidence and prevalence of NTM-PD are increasing [1, 2]. The incidence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis widely varies depending on geography [3]. Although the number of reported cases is small and detailed information is lacking, NTM associated with MPA is not as uncommon as originally considered. There is currently no established treatment. We herein successfully treated a patient admitted with renal impairment and diagnosed with MPA associated with NTM-PD.

Case report

A 72-year-old Japanese male was admitted to our medical unit with fever, arthralgia, and a non-productive cough. His previous medical history included NTM-PD and bronchiectasis that presented 20 years ago. He had no history of smoking. He was diagnosed with myelodysplastic syndrome (MDS) 1 year prior to admission, which was successfully treated with cyclosporine. The patient had received treatment for M. intracellulare-induced NTM-PD 7 years ago. The diagnosis of NTM-PD was established based on computed tomography (CT) findings and elevated MAC antibodies, because a sputum culture was not feasible due to the patient’s ongoing prophylactic use of levofloxacin (Fig. 1). A very low blood level of IFN-γ level (< 0.1 IU/mL) was noted in specific testing for further assessments. Chest CT showed a cavernous shadow, chronic bronchitis, and a solid lesion in the right lung, which were consistent with NTM-PD. Treatment for NTM-PD was initiated with clarithromycin (800 mg daily), rifampicin (450 mg daily), and ethambutol (750 mg daily) 2 weeks before admission. Ethambutol was reduced to a dosage of 500 mg every other day due to elevated creatinine levels on the day of admission. However, the treatment for NTM-PD was not adjusted during the management of ANCA-associated vasculitis, because NTM-PD did not worsen despite the patient receiving immunosuppressive therapy. Diffuse ground glass opacities were observed in both lungs as the pulmonary manifestation of MPA. Laboratory tests revealed elevated creatinine (2.36 mg/dL) and MPO-ANCA (611 U/mL). Based on these findings, MPA was suspected and renal biopsy was performed. Approximately 7% of glomeruli exhibited global sclerosis, while 60% showed cellular crescents in Bowman’s space and fibrinoid necrosis on glomerular tufts. Inflammatory cell infiltration was observed in the interstitial architecture. However, no evidence of vasculitis was detected in the arteries or arterioles (Fig. 2). Based on these findings, the patient was diagnosed with MPA (Table 1). The Birmingham Vasculitis Activity Score was 12. Intravenous glucocorticoid therapy (methylprednisolone (mPSL) 500 mg daily for 3 days) was initiated, followed by oral glucocorticoid therapy (30 mg per day as an initial dose). RTX and plasma exchange (PE) (14 sessions) were started in conjunction with systemic glucocorticoid therapy. Since MPO-ANCA (108 U/mL) and creatinine (2.4 mg/dL) remained elevated, the patient was intravenously administered a glucocorticoid as additional therapy (mPSL 250 mg daily for 3 days). Although the cavernous shadow, chronic bronchitis, and solid lesion in the right lung did not improve after treatment with steroids, RTX, and PE, the marked attenuation of diffuse bilateral ground glass opacities was achieved. The patient was discharged after 43 days of hospitalization. The corticosteroid dose was gradually tapered to a maintenance dose during the follow-up. Two months after discharge, creatinine and MPO-ANCA had decreased (Fig. 3).

Fig. 1.

a, b A CT scan performed on admission showed a cavernous shadow, chronic bronchitis, and a solid lesion in the right lung, which were consistent with NTM-PD (as shown by the red arrows). Ground glass opacities were detected in both lungs as the pulmonary manifestation of MPA (as shown by the yellow arrows). c, d A CT scan performed 4 weeks after the initiation of treatment with steroids, rituximab, and plasmapheresis showed the marked attenuation of bilateral diffuse ground glass opacities

Fig. 2.

a A representative glomerulus showing a cellular crescent in Bowman’s space. b The interstitial architecture shows inflammatory cell infiltration. c The glomerulus shows fibrinoid necrosis

Table 1.

Summary of blood and urine test results

TP	7.2	g/dL	WBC	106 × 102	/μL
Alb	2.6	g/dL	Neu	73.4	%
BUN	34	mg/dL	Lym	13.8	%
Cre	2.36	mg/dL	Mono	9.8	%
AST	18	IU/L	Eosin	2.8	%
ALT	24	IU/L	Baso	0.2	%
LD	208	IU/L	RBC	230 × 104	/μL
CK	45	IU/L	Hb	7.4	g/dL
TG	102	mg/dL	PLT	15.7 × 104	/μL
T-cho	195	mg/dL	IgG	1370	mg/dL
LDL-C	133	mg/dL	IgA	490	mg/dL
CRP	17.56	mg/dL	IgM	64	mg/dL
Na	138	mEq/L	IgE	121	IU/mL
K	4.4	mEq/L	MPO-ANCA	611	U/mL
Cl	102	mEq/L	PR3-ANCA	< 1.0	U/mL

pH	5.5
Urine protein	+
Urine occult blood	3+
RBC	307.8	/HPF
U-TP/U-Cr	1.03	g/gCr

Fig. 3.

Clinical course on admission. After prednisolone, rituximab, and PE were initiated, MPO-ANCA and creatinine gradually decreased. However, since both remained elevated, a glucocorticoid (methylprednisolone 250 mg daily for three days) was added

Discussion

Myelodysplastic syndrome (MDS) is frequently associated with vasculitis [4, 5]. Abnormalities in both the cell-mediated and humoral immune systems have been observed in patients with MDS. Furthermore, natural killer cell activity was found to be significantly reduced in the peripheral blood of MDS patients [6, 7], while polyclonal serum immunoglobulin levels were elevated in some patients [5]. This increase may be attributed to elevated numbers of monocytes, which secrete cytokines that promote B cell proliferation, such as interleukin 1. Some patients with MDS also have autoantibodies due to B cell hyperactivity [5, 8]. ANCA may have occurred in the present case through the same mechanism. These immune system abnormalities may contribute to the development of vasculitis in MDS patients. The present case had received cyclosporine as immunosuppressive therapy. During the treatment of ANCA-associated vasculitis, the concurrent use of cyclosporine is associated with a risk of excessive immunosuppression. Therefore, the decision was made to opt for ANCA-targeted therapy alone. NTM infections affect various parts of the body, including the lungs and areas outside of the lungs [9]. MAC, M. kansasii, and M. abscessus are common NTM. MAC pulmonary disease is treated with triple therapy (macrolides, ethambutol, rifampicin). According to the ATS/ERS guidelines, an intermittent dosing regimen of three drugs administered three times a week is recommended for non-cavitary nodular/bronchiectatic disease. On the other hand, a daily regimen of the three drugs is the standard of care for cases exhibiting cavities or advanced bronchiectatic changes or those with a high bacterial load, with the addition of the intravenous or intramuscular administration of aminoglycosides during the initial phase of treatment depending on the individual case. Treatment for M. kansasii is conducted using a three-drug regimen consisting of rifampicin, ethambutol, and either isoniazid or a macrolide. Quinolones and aminoglycosides are generally unnecessary in this context. M. abscessus is one of the most pathogenic NTMs, particularly in those with underlying lung disease [10]. Limited information is available on optimal antibiotic regimes and the long-term outcomes of chronic suppressive treatment. MPA is characterized by the inflammation of blood vessels, which may restrict blood flow and damage vital organs and tissues. Due to the severity of the present case with rapidly progressive glomerulonephritis, RTX and PE were initiated with systemic glucocorticoid therapy. RTX is effective for active severe disease, as indicated by the 2021 American College of Rheumatology/Vasculitis Foundation Guidelines. Two high-quality randomized controlled trials on new-onset MPA showed that RTX was not inferior to cyclophosphamide (CYC) for the induction of remission [11, 12]. There has been an increasing preference for RTX over CYC, mostly because of concerns regarding the long-term safety of CYC [13], which has been associated with the development of bladder cancer and other malignancies [14, 15]. PE is considered for MPA patients with active glomerulonephritis in the ACR guidelines [16]. The clinical condition of the present case markedly improved with treatment. However, MPO-ANCA and creatinine remained elevated after treatment as opposed to other cases of MPA, which may be relevant to NTM-PD. Therefore, a glucocorticoid (mPSL 250 mg daily for 3 days) was intravenously administered as additional therapy. Excessive humoral immune responses secondary to circulating immune complexes have been implicated in the relationships between vasculitis and chronic suppurative lung conditions [17]. MPA was caused by NTM-PD, because prolonged infection by NTM may induce ANCA antigen expression on the surface of neutrophils [18]. In the present case, MPA secondary to NTM-PD was not etiologically related, it was an incidental complication. This was supported by the only two reported cases of MPA associated with NTM-PD, despite the increased prevalence of NTM-PD. Increased susceptibility to NTM-PD has been reported in genetic interferon defects; however, a causal link with vasculitis has not been established [19]. One of the reported cases suggested that the reduced level of IFN-γ contributed to a poor treatment response. IFN-γ is essential for defense against mycobacterial infections through the activation of the immune system, because it promotes phagocytosis and the expression of oxygen free radicals to kill mycobacteria [19, 20]. In that case, difficulties were associated with the management of vasculitis, including therapeutic challenges, due to a very low level of IFN-γ [18]. A reduced IFN-γ level was also observed in the present case, which required additional steroid therapy. Therefore, MPA secondary to NTM-PD may be refractory in the presence of a very low level of IFN-γ. In contrast, the other case report showed the marked amelioration of vasculitis with steroid monotherapy [21]. However, since the exact level of IFN-γ was not described, it was unlikely to be very low due to the favorable response to treatment. Further studies are needed to confirm a causal link between vasculitis and NTM-PD.

Abbreviations

NTM-PD

Non-tuberculous mycobacterial-pulmonary disease

MPA

Microscopic polyangiitis

MPO-ANCA

Myeloperoxidase antineutrophil cytoplasmic antibody

IFN-γ

Interferon-gamma

NTM

Non-tuberculous mycobacteria

MAC

Mycobacterium avium Complex

ANCA

Antineutrophil cytoplasmic antibody

MDS

Myelodysplastic syndrome

CT

Computed tomography

RTX

Rituximab

PE

Plasma exchange

CYC

Cyclophosphamide

mPSL

Methylprednisolone

Declarations

Conflict of interest

All the authors have declared no competing interests.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from the patient in the present study.