A 40-year-old man was admitted to the Rheumatology Department of the Second Affiliated Hospital, Fujian Medical University, on October 8, 2021, with the main complaints of 4-year pulmonary nodules and 3-year repeated haemoptysis. Four years before admission (January 2017), the patient visited a local hospital for trauma (specific unknown). Pulmonary CT revealed multiple bilateral pulmonary nodules and mass shadows, inflammatory flaked shadows and significantly thickened pleura. Lung biopsy pathology showed granulomatous inflammatory flaked necrosis. Pulmonary tumours were excluded according to immunohistochemical findings. At follow-up, pulmonary CT demonstrated more pulmonary nodules and flaked shadows. The patient had no previous underlying diseases, such as hypertension, nor a bad habit of smoking.
On June 2017, the patient visited a tertiary hospital in Beijing, China, due to low fever, joint pain and maculopapular rash. Laboratory examination showed an erythrocyte sedimentation rate (ESR) of 47 mm/h; C-reactive protein (CRP) level of 18.6 mg/L; rheumatoid factor (RF) level of 225 IU/ml; normal levels of antinuclear antibodies (ANAs), anti-ENA antibodies, anti–double-stranded DNA antibodies, immunoglobulins (IgA, IgM, IgG), complement and anti-cyclic citrullinated peptide (CCP) antibodies; and C-ANCA and PR3-ANCA positivity. AAV was considered. Immunosuppression was obtained using methylprednisolone (80 mg/d) plus cyclophosphamide 0.2 g qod. In addition, human Ig (20 g/d) was administered for 5 days with satisfactory results. Some pulmonary lesions disappeared, while the inflammatory indicators remained at a high level. After discharge from the hospital, the patient’s maintenance regimen consisted of oral prednisone 20 mg/d combined with cyclophosphamide 0.2 g qod.
On July 2018, the patient returned to the tertiary hospital for cough and haemoptysis. He was positive for C-ANCA and exhibited significantly increased inflammatory levels, more pulmonary nodules and mass shadows. According to the 2017 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for granulomatosis with polyangiitis, GPA was diagnosed. Anti-inflammatory methylprednisolone 40 mg/d and oral cyclophosphamide (150 mg for one day and 100 mg for two consecutive days) were administered. The symptoms improved, while there was intermittent cough and shortness of breath after activity.
On August 13, 2018, the patient visited our hospital with the main complaint of cough with yellow sputum. Laboratory examination revealed a white blood cell count of 11.8×10^9/L, neutrophil count of 7.6×10^9/L, and lymphocyte count of 2.6×10^9/L. Analysis of lymphocyte subsets showed the following results: B lymphocyte antigen 4.1% (10-15%), CD4 35.1% (25.8-41.6%), CD8 52.2% (18.1-29.6%), and CD4/CD8 0.67. In addition, the patient exhibited C-ANCA positivity, PR3-ANCA 94.86 nmol/l (<20 nmol/l), ESR 55 mm/H (normal, <15), CRP 14.1 mg/L (normal, <0.5), IL-6 17.11 pg/ml (normal, <7), and normal procalcitonin (PCT). Negative results were obtained for the sputum culture serum G ((1–3)-β-d-glucan), galactomannan (GM), Cytomegalovirus (CMV), EB virus and T-spot tests. Nine respiratory pathogen antibody IgM tests, namely, tests for Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, Rickettsia Q fever, influenza A and B viruses, parainfluenza virus, respiratory syncytial virus, and adenovirus, were normal. On pulmonary CT, multiple patchy shadows, nodular higher-density shadows, multiple cavities, heterogeneous wall thickness, air crescent signs and flat lipids in some lesions were observed (Figure 1A). After Respiratory Department consultation, the possibility of lung infection (bacteria+fungi) was considered. Pneumocystis infection could not be ruled out. Cyclophosphamide was discontinued, and the hormone doses were reduced. In addition, moxifloxacin antibacterial, voriconazole antifungal and prophylactic anti-Pneumocystis jiroveci treatments were administered for two weeks with improved symptoms and decreased inflammatory levels. After discharge, cyclophosphamide 100 mg was administered on alternate days, with a cumulative dose of 28 g. During the outpatient follow-up, the inflammatory marker levels were within the normal range, and the pulmonary lesions increasingly disappeared. However, the G test was positive twice, while the GM test was negative. The vasculitis was considered to be controlled, but the pulmonary fungal infection persisted. Dose reduction was obtained, and methylprednisolone 6 mg/d was administered. Cyclophosphamide was replaced with TW for immunosuppression. Oral antifungal agents were concurrently administered and discontinued within one year.
On March 19, 2019, September 5, 2019, November 23, 2019, and June 12, 2020, the patient visited the Rheumatology Department of our hospital for fever, fatigue and systemic muscle soreness. Laboratory examination revealed increased CRP and ESR levels, IL-6 33.43 pg/ml, and normal PCT. EB DNA was 5.09E+4↑copies/ml. Negative results were obtained for the pathological examination of tracheal lavage fluid, and TORCH test analysis of lymphocyte subsets revealed B lymphocytes (CD3-CD19+) 2.5% (62/µl) and CD4/CD8 0.6. On pulmonary CT, there were new and larger bilateral pulmonary nodules (Figure 1B). Anti-infectious moxifloxacin and antiviral peramivir were successively applied. The body temperature was normal, while the sensation of fatigue was retained. Elevation of the PR3-ANCA titre was examined, considering vasculitis activity. Since the patient had a low level of B lymphocytes and a history of deep mould infection, rituximab was not recommended. Therefore, the treatment plan was changed to a glucocorticoid dose increase combined with MMF. The patient's fatigue symptoms improved. PR3-ANCA and inflammatory marker levels decreased.
On September 15, 2020, the patient was treated at the Rheumatology Department of our hospital again for fatigue, muscle soreness at the extremities and joints, cough with yellow sputum and shortness of breath. He exhibited CRP 51.09 mg/L, ESR 84 mm/H, C-ANCA positivity, PR3–ANCA (++), and G-test, GM-test, cryptococcal antigen and TORCH test negativity. Pulmonary CT demonstrated more bilateral pulmonary nodules and cavities and some larger nodular lesions. Renal CT showed a space-occupying lesion in the right middle kidney. Puncture pathology of the space-occupying lesion revealed fibrous tissue proliferation with infiltration of tissue cells, plasma cells and lymphocytes, focal necrosis and no IGG4-positive plasma cell infiltration（Figure 2A/2B）. Vasculitis activity with the involvement of the kidney was considered. Referring to the literature, we noted that the level of circulating B lymphocyte factor increases in patients with AAV. Given the role of the B lymphocyte factor in the onset of AAV, the patient was treated with methylprednisolone 40 mg/d combined with MMF 500 mg bid and belimumab 840 mg (I.V.). The symptoms improved, but the fatigue and soreness at the extremities relapsed due to the dose reduction of hormones.
On March 21, 2021, the patient was admitted to our hospital for haemoptysis. Pulmonary CTA manifestations were normal, while the air crescent sign was observed on CT scan. The haemoptysis was then considered a result of pulmonary infection. MMF and belimumab were discontinued. Anti-infectious moxifloxacin was administered. There was no evidence of recurrence while reducing the use of glucocorticoids, and more pulmonary lesions disappeared. After discharge, the patient was treated with belimumab 840 mg (I.V.) once every month for a total of 8 times. Then, renal CT was performed and revealed a space-occupying lesion in the right middle kidney, which was larger than before (Figure 1C). In the meantime, the pulmonary nodules and cavities were similar. The patient experienced repeated elevation of inflammatory indicators, with a poorly controlled disease. The IL-6 level during the treatment was high, ranging between 32 and 49 pg/ml. Referring to the literature, tocilizumab 640 mg (I.V., once monthly) was administered. After dose reduction of the hormones, there was no evidence of recurrence of fatigue or muscle soreness at the extremities and joints. In addition, the right middle kidney-occupying lesion was smaller (Figure 1D), and the ESR recovered to normal (Figure 3).
On October 8, 2021, the patient was admitted for recurrent haemoptysis without apparent cause. Arteriography demonstrated more and thickened bilateral bronchial arterial branches. Second-generation gene sequencing revealed growth of Pseudomonas aeruginosa in bronchoalveolar lavage fluid. Mixed infection (bacteria+fungi) was suspected. The bacteria were sensitive to piperacillin sodium and tazobactam sodium administered by injection. Tocilizumab was discontinued, and anti-infection therapy was administered due to drug susceptibility. There was no haemoptysis, and the infection was controlled. Tocilizumab was continued at 640 mg (I.V.) once every month, in combination with methylprednisolone 12 mg/d. After treatment, there was no fatigue or muscle soreness, while there was occasional cough with yellow sputum. The patient was discharged after improvement on November 5, 2021. The ESR was normal (Figure 3), and the levels of IL-6 (Figure 4) and PR3-ANCA (Figure 5) were decreased after the use of tocilizumab. The patient remains under outpatient follow-up. His general condition is normal, and his indicator levels are relatively stable.