Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease
A 65-year-old man, originating from northern Greece but living in Sweden for over 30 years, had been referred to the Hematology Center Karolinska for a consultation concerning suspected Gaucher disease. His past medical history was significant for several co-morbidities (). Because of splenomegaly (18 cm) and mild thrombocytopenia, a bone marrow (BM) examination was performed at the age of 51, disclosing the presence of foamy macrophages classified as Gaucher cells (GCs). However, further investigations aimed at the confirmation of GD diagnosis were not performed at that time.\nAt the age of 54 years, he developed malaise and a chronic cough. He was a smoker for 25 years but quit at the age of 50. Radiological examination disclosed mild pulmonary fibrosis and aspergillosis in the right lung. The microbiological examination of secretions from a bronchoalveolar lavage (BAL) showed growth of Aspergillus fumigatus and mycobacteria other than tuberculosis (MOTT). Antifungal therapy with itraconazole (100 mg 2 × 2 p.o.) was administered for 6 weeks, but the MOTT infection was not treated. Of note, several weeks after therapy onset, the patient's clinical course was complicated by pulmonary bleeding (the coagulation work-up was normal apart from moderate thrombocytopenia). The fungal infection did not fully respond to therapy, and 2 years after diagnosis the patient underwent a partial resection of the right lung due to an aspergilloma (). After surgery, his general status improved rapidly.\nAt age of 59, the patient developed shortness of breath and cough. Echocardiography showed septal left ventricular hypertrophy, normal systolic function of the left ventricle (EF of 50%–60%), signs of diastolic dysfunction, mild insufficiency of both aortic and pulmonary valves, and a slightly elevated pressure in the pulmonary artery (PA) of 42 mmHg. Repeated microbiological examination of the BAL secretions revealed a growth of Aspergillus fumigatus and Aspergillus nidulans, but was negative for MOTT. HIV serology was negative, excluding acquired immunodeficiency syndrome (AIDS). Voriconazole was administered for aspergillosis periodically for 2 years (at the age 61–62 years). Afterwards, the patient's symptoms regressed, and control spirometry showed only moderately decreased results (VC 3.72 L, 82%; FEV1 3.04 L, 84%; FEV1/SVC 82%; FVC 3.72 L, 82%). Chest X-ray did not show any active pathological lesions. However, computed tomography imaging (CT) revealed pronounced fibrosis of lung parenchyma.\nAt the time of hematologic consultation (at the age of 65), thrombocytopenia and hyperferritinemia were noted. The final diagnosis of GD1 was confirmed by the absence of glucocerebrosidase activity in peripheral blood leukocytes and an increased activity of plasma chitotriosidase. Further direct DNA sequencing of the GBA1 gene revealed heterozygous mutations in the GBA1 gene ().\nThe patient's status consisting of splenomegaly, thrombocytopenia, and an increased susceptibility to pulmonary infections, which was probably due to lung involvement in the course of GD, was assessed as an indication for commencing treatment of GD. The patient was started on miglustat, which was considered the first line of GD1 treatment at that time due to the worldwide supply shortage of Cerezyme® during 2009–2010 (). He received the commercially available miglustat capsules at a dose of 100 mg three times a day orally.\nInterestingly, the patient experienced an unusually rapid improvement of the whole blood platelet count (PLT), which normalized already after 2 months of miglustat therapy. Unfortunately, the patient developed malaise, diarrhea, poor appetite, weight loss (10 kg, 16% of his baseline body weight), and mild tremor for which miglustat was deemed accountable. During this time, the patient also developed cough, and a microbiological examination of the BAL secretions revealed growth of Aspergillus fumigatus (sensitive to voriconazole) and Mycobacterium avium. Inflammatory activation was observed at that time as presented in .\nThe patient discontinued miglustat after 4 months of treatment due to the adverse events and the above-mentioned pulmonary infections. Voriconazole was administered, and after 10 days his cough decreased but, after some days, returned, alongside malaise and night sweats. CT of the chest disclosed a new infiltrate in the lower lobe of the right lung, despite antifungal therapy (). Treatment with rifampicin, ethambutol, and clarithromycin for Mycobacterium avium was initiated. After 4 months of therapy, the patient was stronger, his cough and night sweats were clearly reduced, and he had regained 10 kg of body weight.\nAfter the Cerezyme® supply shortage had ceased, the patient was offered to start ERT. Unfortunately, he strongly refused administration of ERT despite our recommendations. Now, almost 2.5 years after the initiation of the triple therapy, and with intermittent periods of negativity, the patient is recurrently positive for Mycobacterium avium in his sputum, despite 8 months of triple therapy administered during the preceding year. During the periods of deterioration in his general condition, he was also positive for Aspergillus fumigatus in sputum.