Pulmonary Nocardiosis in a Multiple Myeloma Patient Treated with Proteasome Inhibitors

Background

Proteasome inhibitors (PI) are being increasingly used to treat multiple myeloma (MM). They have been shown to reduce antigen processing and CD8 T cell function vital for cell-mediated immunity. PI bortezomib has been associated with increased rates of opportunistic infections when severe lymphopenia is present. Carfilzomib is a novel PI approved for the treatment of refractory MM for which the prevalence of opportunistic infections is not known. We report a case of pulmonary nocardiosis in a patient with refractory MM being treated with Carfilzomib chemotherapy.

Case Report

A 71-year-old man with MM presented with a 6-week history of fever and cough. He was diagnosed with MM 6 years before presentation and underwent autologous stem cell transplantation followed by lenalidomide maintenance. He relapsed and dexamethasone with bortezomib was added to his treatment. Due to breakthrough disease (8 weeks before admission), he was started on carfilzomib and received 13 cycles. Two weeks into therapy he developed transient low-grade post-chemotherapy fever and progressive dyspnea. He denied involvement in outdoor work or exposure to soil and had no weight loss, seizures, headache, focal weakness, skin abscesses, or ulcerations

On admission, he was febrile and tachypneic. Examination was significant for diminished breath sounds over the right mid- and lower lung zones. WBC count was 6500/mcl with 90% neutrophils and 1% lymphocytes. CT angiography ruled out pulmonary embolism, but revealed a mass-like consolidation in the right lower lobe, with bilateral airspace consolidations (Figure 1). Bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies were negative for malignancy; however, respiratory cultures grew Nocardia abscessus.

He was treated with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) and meropenem. Repeat CT showed a significant decrease in the mass-like lesion on the right, now with cavitation and resolution of the airspace consolidations (Figure 2) within a period of 3 weeks. He was discharged on trimethoprim-sulfamethoxazole and minocycline with close follow-up. Unfortunately, he returned with a fever and CT evidence of worsening right lower lobe consolidation. Treatment with intravenous meropenem and TMP-SMX were restarted. Malignancy was excluded by a CT-guided biopsy. Due to concerns that TMP-SMX were contributing to leukopenia, it was changed to tigecycline. He showed dramatic clinical improvement and was discharged to complete 42 days of intravenous tigecycline and meropenem while awaiting final Nocardia sensitivities. Close follow-up with the Infectious Diseases Department and Oncology was scheduled. He is currently on a chemotherapy regimen of Dexamethasone, Bortezomib, and Panobinostat for the treatment of MM.

Discussion

Nocardia produces a life-threatening infection in patients with defective cell-mediated immunity, with a high propensity for delayed diagnosis because of the non-specific presentation and radiographic findings. In addition to the severe morbidity, including its predilection for the CNS, the diagnosis often involves prolonged courses of antibiotics and associated toxicities. There are multiple risk factors that predispose patients to infection with Nocardia, and conditions or medications that suppress cell-mediated immunity predominate. Multiple myeloma causes immune deficiency mainly through B-cell dysfunction.

Proteasomes are large protein complexes in nucleated cells that bind and degrade ubiquitinated proteins, thus helping, along with lysosomes, to maintain protein homeostasis. Malignant cells are highly dependent on this pathway. Proteasome inhibitors cause buildup of substrates, disrupt signaling pathways, and arrest cell cycle progression. Proteasome inhibitors like Bortezomib have been shown to have numerous effects on the immune system [1], which are all vital for cell-mediated immunity. They decrease proliferation and viability of T cells [2,3] and the number and function of NK and CD8 T cells [4].They impair antigen presentation, dendritic cell function [5,6], and alter cytokine secretion [7]. The use of bortezomib has been associated with increased incidence of opportunistic infections, including Nocardia, within the treatment period when severe lymphopenia is present [8,9]. Unlike bortezomib, whose effect is slowly reversible, carfilzomib exhibits irreversible inhibition of proteasome activity. The onset of action is similar but its effect is more sustained and specific [10]. In our patient, the lymphocyte count during admission was 1%, likely induced by carfilzomib and bortezomib, which may have contributed to Nocardia infection. In addition, the patient was also on dexamethasone, which contributed to the overall state of immunosuppression and perhaps the predisposition to nocardiosis.

Conclusions

Based on our case and recent reports of nocardiosis, there may be a role for close clinical monitoring in patients with severe lymphopenia who are treated with proteasome inhibitors for opportunistic nocardiosis.

With advancements in the treatments for multiple myeloma, clinicians must have a high degree of suspicion for the development of opportunistic infections, including Nocardia, in an effort to achieve early and effective diagnosis and treatment.