Is ibrutinib associated with disseminated cryptococcosis with CNS involvement?

Chronic lymphocytic leukemia (CLL) is a disorder of B cells that affects humoral as well as cell-mediated immunity. Protection against cryptococcal infections is mounted by an intricate and synchronized interplay of both integral arms of immunity. Whether CLL or small molecule tyrosine kinase inhibitors are independently predisposing hosts to cryptococcal infections remain to be explored. Herein, we present a report of a patient who developed disseminated cryptococcosis while receiving ibrutinib therapy for CLL in the salvage setting. We further present relevant literature available thus far on the topic and discuss immunologic mechanisms that may be involved in the fungal pathogenesis in such patients.

Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature.

We report a case of Cryptococcus neoformans pulmonary infection complicated by empyema in a 79-year-old man with diffuse large B-cell lymphoma treated with R-CHOP and ibrutinib. A literature review identified 25 cases of cryptococcal pleural disease published since 1980. Most cases were caused by the C. neoformans species in immunocompromised hosts with an exudative pleural effusion and lymphocyte-predominant infiltrate. The cryptococcal antigen test was often positive when pleural fluid and serum were tested. The outcome was favourable in most cases with antifungal therapy and either thoracocentesis or surgical resection. We also identified 40 cases of opportunistic infections, most commonly aspergillosis, cryptococcosis and Pneumocystis jirovecii pneumonia, in patients treated with ibrutinib. In vitro studies indicate Bruton tyrosine kinase inhibition impairs phagocyte function and offer a mechanism for the apparent association between ibrutinib and invasive fungal infections.

Multiple unusual lung etiologies in a child with acute lymphocytic leukemia.

Granulomatous lung disease is a rare and perplexing differential in pediatrics. Pulmonary Cryptococcus falls into the differential but is not high on the list, particularly in a non-AIDS patient. Methotrexate (MTX) is a commonly used agent for chemotherapy in oncology and has been documented to cause lung injury in both patients with rheumatologic and oncologic diseases. Our patient had chronic cough and then developed an opportunistic infection resulting in respiratory failure. Lung biopsy showed two underlying unusual diagnoses: MTX lung injury and cryptococcal pneumonia. His case is presented with particular attention to his prolonged road to diagnosis.

Pulmonary Cryptococcosis in the Setting of Tofacitinib Therapy for Psoriasis.

Tofacitinib is a novel drug that inhibits the JAK-STAT signaling pathway. It has been approved for the treatment of psoriatic arthritis and it is under investigation for the treatment of psoriasis and other inflammatory disorders. We report a case of pulmonary cryptococcosis in an otherwise immunocompetent patient taking tofacitinib for psoriasis. We hypothesized that tofacitinib contributed to this infection through inhibition of cytokines required for differentiation of T cells and suppression of macrophage activation. As dermatologists begin to use this drug they should be aware of the potential for cryptococcocal infection, because delay of diagnosis may increase the risk of a life-threatening outcome.

An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor.

We report a case of Cryptococcus neoformans pneumonia in a patient taking ruxolitinib, a janus kinase 1,2 inhibitor approved for the treatment of myelofibrosis. We hypothesize that ruxolitinib contributed to this infection through its effects on cell-mediated immunity. Clinicians should be aware of the potential for intracellular or opportunistic infections associated with this novel drug class.

Successful treatment of disseminated cryptococcal infection in a pediatric acute lymphoblastic leukemia patient during induction.

Disseminated cryptococcal infection is rarely reported in the setting of pediatric acute leukemia, despite the immunocompromised state of these patients. However, when present, disseminated cryptococcal infection poses treatment challenges and is associated with significant morbidity and mortality. Treatment of invasive fungal disease in a child with acute leukemia requires a delicate balance between antifungal and antineoplastic therapy. This balance is particularly important early in the course of leukemia, as both the underlying disease and overwhelming infection can be life threatening. We describe the successful management of life-threatening disseminated cryptococcosis in a child with acute lymphoblastic leukemia during induction therapy.

Adalimumab-associated pulmonary cryptococcosis.

This is the first report of adalimumab-associated pulmonary cryptococcosis. A 56-year-old female with rheumatoid arthritis without a history of pulmonary disease was simultaneously administered adalimumab (40 mg/2 wks), methotrexate (4 mg/wk), and isoniazid (200 mg/day). Five months later, chest radiography revealed a small spiculated pulmonary nodule, and the laboratory test results, including levels of tumor markers and plasma ß-D-glucan, were within normal ranges. Since the lesion continued to grow, even after discontinuing adalimumab, it was surgically resected. Grocott staining of the tissue sample revealed black-brown fungi, identified as Cryptococcus neoformans in culture. The patient now remains well, without adalimumab therapy.