This article is mentioned in:

Introduction

Nocardiosis is a rare but severe suppurative infection, most commonly seen in susceptible patients with underlying chronic diseases, such as those undergoing tumor chemotherapy, those suffering from alcoholism, or those with endogenous or iatrogenic immunosuppression (1,2). It has been reported that patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis become infected with Nocardia after immunosuppressive therapy, with high mortality rates due to ineffective treatment (3-5). For such patients, it was necessary to control the target organ damage caused by the primary vasculitis, as well as to actively treat the opportunistic nocardial abscesses, which makes the clinical treatment very challenging. In the present study, the case of an elderly patient presenting with typical multiple large nocardial abscesses with ANCA-associated vasculitis and renal insufficiency, who was treated with glucocorticoid and cyclophosphamide, is reported. After medical and surgical therapy, the abscesses were completely absorbed, the patient became negative for ANCA and renal function was completely recovered after 1 year of follow-up. In addition, the present study reviews the literature with regard to the age, clinical characteristics, specific treatment options and treatment outcomes of patients with this rare infection caused by nephropathy and immunosuppressive therapy, in order to improve the outcome of this life-threatening infection.

Case report

A 69-year-old male patient was admitted to the Department of Geriatrics of the Affiliated Hospital of Nantong University (Nantong, China) in September 2020 due to recurrent lower abdominal pain for 1 month. On admission, the patient presented with persistent dull pain in the lower abdomen accompanied by poor appetite and fatigue, without any other complaints of discomfort. The patient was previously healthy. Physical examination showed that temperature, pulse, respiration and blood pressure were normal. Emaciation and anemia were also observed. The breath sounds from both lungs were coarse, but no rales were detected. The whole abdomen was soft, with mild tenderness around the umbilicus and lower abdomen, without rebound pain and muscle tension, and with mild edema in the bilateral lower extremities. Cardiovascular and nervous systems were normal. Blood test results after admission showed the following results: Hemoglobin, 77 g/l (normal range, 120-160 g/l); serum albumin, 28 g/l (normal range, 35-55 g/l); serum creatinine, 242 µmol/l (normal range, 64-104 µmol/l); erythrocyte sedimentation rate, 108 mm/h (normal range, 0-10 mm/h); C-reactive protein (CRP), 105 mg/l (normal range, 0-8 mg/l); and 24-h urine protein, 1.38 g/day (normal range, 0-0.15 g/day). Chest CT showed interstitial inflammation in the bilateral inferior lungs (Fig. 1A). The titer of myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) was 1,573 AU/ml (normal range, <100 AU/ml) using the AtheNA Multi-Lyte® Autoimmune Vasculitis Plus Test System (cat. no. 22020054; Zeus Scientific, Inc.). Thereafter, the patient was transferred to the Department of Nephrology. The patient refused a renal biopsy, and the diagnosis was ANCA-associated vasculitis, renal insufficiency, interstitial pneumonia and moderate anemia. After 5 days of an intravenous infusion of 40 mg methylprednisolone, the treatment was changed to oral prednisone acetate (15 mg three times a day), and 0.6 g cyclophosphamide (CTX) was intravenously administered once. The patient was discharged at 16 days post-admission, and instead was prescribed oral prednisone and monthly intravenous CTX medication, and the dose of corticosteroid was gradually tapered. After 6 months of treatment, the dosage of prednisone acetate was tapered to 25 mg once a day, and the total CTX dosage in 7 months was 4.2 g.

Figure 1 Nocardia infection and chest CT scan results before and after treatment. (A) In September 2020, when the patient was initially diagnosed with anti-neutrophil cytoplasmic antibody-related vasculitis, the chest CT scan showed interstitial inflammation in both inferior lungs. (B) In April 2021, the patient developed pain in the left hip, and a plain chest CT scan on the first day of admission indicated a new left encapsulated pleural effusion. (C) At 12 days after admission, during the hospitalization for the diagnosis and treatment of Nocardia infection, a repeat plain chest CT scan indicated a small amount of bilateral pleural effusion, and the left region was encapsulated slightly more than before. (D) In May 2021, 11 days after the patient was discharged, a repeat plain chest CT scan indicated that the left encapsulated pleural effusion had completely disappeared.

In April 2021, the patient developed swelling and pain in the left hip. After 6 days, the patient was readmitted to the Affiliated Hospital of Nantong University. The vital signs of the patient were stable and normal, but there was a 15x10-cm mass on the left hip. The local skin temperature was increased, with tenderness and swelling, but there was no obvious redness. There was moderate edema in the bilateral lower extremities. A routine blood test showed the following results: White blood cell count, 8.0x109/l (4.0-10.0x109/l); neutrophils, 79.8% (40-75%); hemoglobin, 82 g/l; urine protein, negative; plasma albumin, 28.8 g/l; serum creatinine, 76 µmol/l; MPO, negative; and serum hypersensitive CRP, 27.5 mg/l. Serum markers of HIV, syphilis and hepatitis were negative. The tuberculin test was also negative. A chest CT scan revealed new left encapsulated pleural effusion and new anterior mediastinal nodules (Fig. 1B). Magnetic resonance imaging (MRI) of the left femur indicated encapsulated fluid signals in the proximal subcutaneous part of the left thigh. The mass measured 132x77x44 mm, with internal separation, peripheral soft-tissue swelling and edema, and was considered to be an infectious lesion accompanied by abscess formation (Fig. 2A). After admission, moxifloxacin sodium chloride (0.4 g/day) was intravenously administered for anti-infection purposes, while the dose of oral prednisone acetate was reduced to 10 mg per day and CTX treatment was discontinued. The patient initially refused surgery and asked for conservative treatment. Therefore, under the guidance of ultrasound, 30 ml was extracted from the subcutaneous abscess at the lateral edge of the left thigh, and the puncture pus was collected for bacterial culture and drug sensitivity testing. A metronidazole sodium chloride injection (5 mg/ml) was applied locally for repeated washing. In addition, 10 g of human albumin was intravenously provided on a daily basis as supportive care. After 5 days of treatment, the mass of the left hip did not improve, the discomfort worsened and the patient agreed to surgical intervention. A local subcutaneous abscess incision and aspiration were performed after orthopedic consultation. During the operation, subcutaneous tissue necrosis and a large amount of pus were observed and removed. Furthermore, closed negative pressure drainage was performed on the wound surface after surgery. Weak acid-fast staining (Fig. 2B) and Gram-positive staining (Fig. 2C) (performed at room temperature for ~20 min) of the aspirated pus showed filamentous Nocardia using a light microscope (Olympus Corporation). Accordingly, the antibiotic was adjusted to linezolid glucose injection, 0.6 g by intravenous drip, twice a day. After 12 days, a repeated chest CT scan revealed a small amount of bilateral pleural effusion, and the left region was encapsulated slightly more than before. The anterior mediastinal nodules were similar to 12 days ago (Fig. 1C). The adjustment of the antibiotic to linezolid glucose injection was not observed to be associated with increased pleural effusion of polyserositis. Based on these results, ultrasound-guided puncture and drainage was performed in the left pleural cavity, which extracted 15 ml of pus, and then a metronidazole sodium chloride injection (5 mg/ml) was applied locally for repeated washing. At 2 days after the drainage procedure (April 2021), the patient insisted on being discharged from the hospital due to financial reasons. After discharge, the patient was provided with linezolid tablets (0.6 g orally, every 12 h) and compound trimethoprim-sulfamethoxazole (TMP-SMX) tablets (0.48 g orally, twice a day) for continuous anti-bacterial treatment, as well as prednisone (10 mg daily) orally for maintenance therapy. Subsequent outpatient review of renal function showed a creatinine level of 120 µmol/l, while there was a negative result for MPO and a repeated chest CT scan indicated that the lung abscess had completely disappeared 11 days after discharge (Fig. 1D). No MRI was performed after discharge due to financial reasons. Thereafter, all antibiotics were discontinued, and prednisone was discontinued after 6 months. The condition of the patient was stable during the 1 year of follow-up after discharge, with MPO results remaining negative and renal function still normal (serum creatinine, 87 µmol/l) (Fig. 3). The patient will have a good prognosis and will be followed up for the next 2 years.

Figure 2 Results of the left femur. (A) Coronal MRI scan of the left femur showed encapsulated fluid under the skin of the proximal segment of the left thigh, and the surrounding soft tissue was swollen, with edema. (B) Weak acid-fast staining of the aspirated pus showed filamentous Nocardia (arrows) using a light microscope (magnification, x1,000). (C) Gram-positive staining of the pus also showed filamentous Nocardia (arrows) using a light microscope (magnification, x1,000).

Figure 3 Changes in the serum creatinine and MPO-ANCA titer levels. After the diagnosis of nocardiosis infection was made, the patient's serum creatinine level showed dynamic changes and no relapse of ANCA-associated vasculitis occurred. MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; TMP-SMX, trimethoprim-sulfamethoxazole; Scr, serum creatinine.

Discussion

Nocardia is an aerobic gram-positive bacterium, belonging to Mycobacteriaceae family, which can infect humans through skin trauma or respiratory inhalation (6). In different types of immunosuppressed populations, the overall incidence of Nocardiosis has been reported as ≤3.6%, while the associated mortality is as high as 77% (7-9). To the best of our knowledge, very few cases of Nocardia infection in elderly patients with ANCA-associated vasculitis have been reported as successfully treated in a short period of time (3-5). The most common site of Nocardia infection is the lung, followed by the skin and the brain (10). Nocardia infection is usually seen in susceptible patients with chronic diseases, or endogenous or iatrogenic immunosuppression (11). In a review of the literature, 15 published cases of Nocardia infection worldwide from the last two decades in patients with underlying renal diseases, such as systemic lupus erythematosus, membranous proliferative glomerulonephritis, nephrotic syndrome or kidney transplantation, were found (3-5,12-23; Table I). Among them, 3 cases were ANCA-associated vasculitis, and only 1 case was reported in China, but 1 case in Japan was successfully treated. The current study is the first case of successful treatment of Nocardia secondary infection with linezolid in an elderly patient with ANCA-associated vasculitis in China. In the present case, the patient was an immunosuppressed elderly male who received glucocorticoid therapy for ANCA-associated vasculitis. Renal insufficiency might also impair normal immune function (24). The risk of Nocardia infection may therefore be higher in older patients with renal insufficiency who are receiving immunosuppressive therapy. The reported patient had the three of the aforementioned risk factors for Nocardia infection. The lungs and skin were simultaneously involved, and the condition manifested as multiple sites of suppurative necrosis and abscess formation, which are typical characteristics of nocardiosis. However, clinical recovery was finally achieved after comprehensive treatment.

Table I Reported cases of Nocardia infection with underlying renal disease and receiving immunosuppressive therapy.

Table I

Reported cases of Nocardia infection with underlying renal disease and receiving immunosuppressive therapy.

First author, year	Country	Age, years	Sex	Type of kidney disease	Clinical syndrome	Immunosuppressive agents	Treatment	Outcome	(Refs.)
McNab et al, 2000	Chile	24	F	Lupus nephritis	Pleuropneumonia and occipital abscess	Cyclophosphamide and prednisone	Cotrimoxazole and cefixime	Deceased	(12)
Lee et al, 2002	South Korea	37	F	Lupus nephritis	Pleural effusion	Methylprednisolone and cyclophosphamide	TMP-SMX	Cured	(13)
Pottumarthy et al, 2003	USA	43	F	SLE	Pulmonary infection	Cyclosporine and prednisone	TMP-SMX	Cured	(14)
Sonesson et al, 2004	Sweden	60	M	ANCA-associated vasculitis	Pulmonary infection and brain abscess	Methylprednisolone and cyclophosphamide	Meropenem	Deceased	(3)
Elmaci et al, 2007	Turkey	49	M	Nephrotic syndrome	Mass lesion in the left lower extremity and brain abscess	Prednisone and cyclophosphamide	TMP-SMX	Cured	(15)
Tilak et al, 2012	India	50	M	Renal transplant	Brain abscess	Cyclosporine, azathioprine and prednisolone	TMP-SMX	Cured	(16)
Lee et al, 2012	South Korea	64	M	Membranous glomerulopathy	Pulmonary infections and mass in the right upper arm	Prednisolone	TMP-SMX	Cured	(17)
Ates et al, 2013	Turkey	40	F	Lupus nephritis	Subcutaneous and brain abscesses	Azathioprine and prednisolone	TMP-SMX and ceftriaxone	Cured	(18)
Patel et al, 2013	India	50	M	Renal transplant	Pulmonary infection	Prednisolone, MMF and cyclosporine	Ceftriaxone and minocycline	Cured	(19)
Weerakkody et al, 2015	Sri Lanka	38	M	Renal transplant	Brain abscess	Tacrolimus and MMF	Imipenem and levofloxacin	Cured	(20)
Grahammer and Fischer, 2015	Germany	71	M	Membranous glomerulonephritis	Pulmonary and i ntramuscular abscesses	Prednisone and MMF	Imipenem, levofloxacin TMP- SMX and linezolid	Cured	(21)
Poisnel et al, 2015	France	51	M	Peritoneal dialysis	Pulmonary and urinary tract infections	Methylprednisolone	TMP-SMX	Deceased	(22)
Hirayama et al, 2016	Japan	68	M	ANCA-associated vasculitis	Pulmonary infection	Cyclophosphamide and prednisolone	TMP-SMX	Cured	(4)
Zhu et al, 2017	China	60	M	Nephrotic syndrome	Pulmonary and cutaneous infections	Cyclophosphamide and methylprednisolone	TMP-SMX and ceftriaxone	Cured	(23)
Wang et al, 2019	China	53	F	ANCA-associated renal vasculitis	Brain abscess	Methylprednisolone	Meropenem + voriconazole → piperacillin sodium/tazobactam → sodium + voriconazole cefoperazone/ sulbactam + micafungin	Deceased	(5)
Present study	China	69	M	ANCA-associated vasculitis	Pulmonary and intramuscular abscesses	Cyclophosphamide and prednisone	Linezolid and TMP-SMX	Cured	-

[i] TMP-SMX, trimethoprim-sulfamethoxazole; SLE, systemic lupus erythematosus; MMF, mycophenolate mofetil; ANCA, anti-neutrophil cytoplasmic antibody; M, male; F, female; →, therapy updated.

Linezolid is a synthetic antibacterial agent of the novel antibiotic oxazolidinone, which is active against most Gram-positive bacteria (25). Linezolid has been reported as a novel second-line drug for Nocardia infection, and is generally well tolerated (26). In the present case, the patient was clinically cured after receiving linezolid treatment for 2 weeks, and no serious adverse drug reactions, such as hematological side effects, lactic acidosis or peripheral neuropathy, were observed, possibly due to the short-term nature of the treatment. Despite the development of various new drugs, including linezolid, in recent decades, sulfonamides remain the first-line therapy against Nocardia infection (27,28), the most representative drug being TMP-SMX; however, drug-resistance has increased over time (29). In the present case, the renal function of the patient was impaired at the time of admission. After treatment of the primary disease with immunosuppressants, and anti-infection treatment with linezolid during hospitalization, the renal function of the patient returned to normal. A therapeutic dose (0.48 g, twice a day) of oral TMP-SMX was added after discharge. During the follow-up, renal function fluctuated in a short period of time, but returned to normal after the TMP-SMX was discontinued. During a year of follow-up, the laboratory test results of the patient were normal.

The present typical case and the related published literature indicate that rare opportunistic infections are not entirely uncommon in immunocompromised patients. Clinicians should be aware of possible Nocardia infection and its tendency to spread when patients present with clinical manifestations of systemic dissemination or locally encapsulated effusion (pus). An early diagnosis of Nocardia infection, and the precise and rational use of sensitive antibiotics can significantly improve the prognosis of this high mortality-associated infection.

Acknowledgements

Not applicable.

Funding

Funding: The present study was funded by the Nantong Science and Technology Project (grant nos. JCZ20060 and MS12021038).

Availability of data and materials

All data generated and/or analyzed during this study are included in this published article.

Authors' contributions

XC and YZ contributed to the conceptualization and design of the study, the collection of clinical information and the drafting of the manuscript. YF analyzed medical images (MRI and CT scans) and patient data, and advised on patient treatment. YF and YZ contributed to critical revisions of the intellectual content and confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Affiliated Hospital of Nantong University (Nantong, China; approval no. #2020-K029).

Patient consent for publication

Written informed consent was obtained from the patient for the publication of the data and images included in the present case report.

Competing interests

The authors declare that they have no competing interests.

References