From Central Valley California

Coccidioidomycosis infection in a patient with Polycythemia Vera on Ruxolitinib. 

Clinical history: 63-year-old male with polycythemia vera, JAK-2 V617F mutation-positive presented with high WBC counts and thrombocytosis. He was managed with hydroxyurea treatment 6 years ago. Bone marrow biopsy two years ago was reported as chronic Idiopathic myelofibrosis. He developed progressive disease uncontrollable thrombocytosis, anorexia, and early satiety from splenomegaly.  The patient was started on Ruxolitinib (Jakafi), a Jak-1, 2 inhibitor, 20mg BID and there was an excellent response with a decrease in the spleen size with improvement in a sense of well-being. After a month the dose of Jakafi had to be lowered because of side effects to 20mg a day. 

After a year of Ruxolitinib treatment, the patient noted shortness of breath and was admitted to the hospital for workup. Chest x-ray revealed bilateral pulmonary infiltrates and the IgG and IgM titers for Cocci infection were positive. Ruxolitinib was discontinued and the patient was started on coccidioidomycosis treatment with Fluconazole. He improved quickly and was no longer short of breath. 

Discussion: Central Valley in California is an endemic area for coccidioidomycosis and the infection frequently presents as community-acquired pneumonia. The fungus can disseminate to the bone, visceral organs, skin, nervous system and the clinical outcome of infections is determined by the host immune response. Immunocompromised patients develop a more severe form of fungal infection as they are not able to mount an effective immune response. 

Jak 1,2 inhibitor, Ruxolitinib is approved for the treatment of polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea and for intermediate or high‐risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF. The drug inhibits the Janus family of kinases which play a central role in developing an immune response to foreign antigens.  It specifically inhibits natural killer cells, dendritic cells, T helper, and regulatory T cells. Due to the blockade of the immune response, the inhibitors have found clinical relevance in auto-immune disorders such as rheumatoid arthritis and for graft versus host disease. Susceptibility to infections has been reported in patients on treatment with ruxolitinib.

Key Points: 

• Patients with myeloproliferative disorders treated with Jak-1,2 inhibitors can develop unusual infections as the Jak family of kinases are important for generating an effective immune response. 

• A number of unusual infections have been reported in patients treated with Jak-1,2 inhibitors such as disseminated tuberculosis, histoplasmosis infection, herpes zoster, and cryptococcus. This case report documents coccidioidomycosis in a patient on Ruxolitinib.

• Jak2 inhibitors (e.g. Rinvoq) are also now approved to treat patients with Rheumatoid arthritis which exposes a large number of patients to a risk of unusual infections in endemic areas.

• Coccidioidomycosis serology testing should be done for patients on Jak-1,2 inhibitors in endemic areas.

Additional Reading: 

1. Lussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib-associated infections: A systematic review and meta-analysis. Am J Hematol. 2018 Mar;93(3):339-347. 

2. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. 

3. Hung CY, Hsu AP, Holland SM, Fierer J. A review of innate and adaptive immunity to coccidioidomycosis. Med Mycol. 2019 Feb 1;57(Supplement_1):S85-S92. 

4. Harigai M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019 Feb 1;58(Suppl 1):i34-i42. 

5. Colombel JF. Herpes Zoster in Patients Receiving JAK Inhibitors For Ulcerative Colitis: Mechanism, Epidemiology, Management, and Prevention. Inflamm Bowel Dis. 2018 Sep 15;24(10):2173-2182. 

6. Colomba C, Rubino R, Siracusa L, et al. Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. BMC Res Notes. 2012;5:552. Published 2012 Oct 5. 

7. Polverelli N, Breccia M, Benevolo G, Martino B et al. Risk factors for infections in myelofibrosis: role of disease status and treatment. A multicenter study of 507 patients. Am J Hematol. 2017 Jan;92(1):37-41. 

8. Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, Cervantes F, Jones MM, Sun K, McQuitty M, Stalbovskaya V, Gopalakrishna P, Barbui T. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016 Aug;30(8):1701-7.

9. Parampalli Yajnanarayana S, Stübig T, Cornez I, et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol. 2015;169(6):824-833. 

10. Schönberg K, Rudolph J, Vonnahme M, et al. JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms. Cancer Res. 2015;75(11):2187-2199. 

11. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122(7):1192-1202. 

12. Yael Kusne, Kathryn E Kimes, Fionna F Feller, Roberto Patron, Juan Gea Banacloche, Janis E Blair, Holenarasipur R Vikram, Neil M Ampel. Coccidioidomycosis in Patients Treated With Ruxolitinib. Open Forum Infectious Diseases, Volume 7, Issue 6, June 2020, ofaa167,