Cryptococcal meningoencephalitis in an IgG2-deficient patient with multiple sclerosis on fingolimod therapy for more than five years – case report

Abstract

Background Fingolimod (Gilenya®), a first-in-class sphingosine-1-phosphate receptor modulator is approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod-induced selective immunosuppression leads to an increased risk of opportunistic infections such as cryptococcosis. So far, a total of 8 cases of fingolimod-related cryptococcal meningoencephalitis have been published. Case presentation A 49-year-old female with relapsing-remitting multiple sclerosis presented with cephalgia, fever, confusion and generalized weakness. She had been on fingolimod therapy for the past 5.5 years. Clinical examination suggested meningoencephalitis and laboratory findings showed an IgG2 deficiency. Initially no pathogen could be detected, but after 4 days Cryptococcus neoformans was found in the patient’s blood cultures leading to the diagnosis of cryptococcal meningoencephalitis. After antimycotic therapy, her symptoms improved and the patient was discharged. Conclusion MS patients on immunomodulatory therapy are at constant risk for opportunistic infections. Cephalgia, fever and generalized weakness in combination with fingolimod-induced lymphopenia should be considered a red flag for cryptococcosis.

Increased risk of disseminated cryptococcal infection in a patient with multiple sclerosis on fingolimod

“…C. neoformans has a special affinity to cross blood brain barrier (BBB), and many mechanisms have been proposed in this regard [ 4 ]. So far, eight cases of meningoencephalitis [ [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] ] have been reported, with 2 reported deaths [ 11 , 14 ] and significant long-term cognitive impairment in one case [ 9 ]. To the best of our knowledge, two cases of disseminated disease have been reported [ 17 , 18 ], with significant permanent neurological and cognitive impairment as sequelae in one patient [ 18 ].…”

“…MRI findings of the brain in Cryptococcus-related meningoencephalitis vary, mostly showing leptomeningeal and parenchymal enhancement [ 19 ], which was not present in our case. Additionally, the reported disseminated and meningoencephalitis cases [ [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] ] showed baseline lesions of MS, with no new lesions and making the early diagnosis difficult. Hence, initial imaging including CT and MRI do not completely rule out the possibility of infection.…”

Dynamic protein quantitation (DyProQ) of procollagen-I by CRISPR-Cas9 NanoLuciferase tagging

“…A proposed mechanism of action is reduced TGF-β stimulated collagen secretion by primary lung fibroblasts 34 . Others included Thioridazine, a first-generation antipsychotic drug and a potential anti-inflammatory 36 ; Mefloquinine, used to prevent malaria but has suspected psychotic side effects 37 ; CEP-18770 (Delanzomib), a proteasome inhibitor with potential anti-tumour activity 38 ; Dacomitinib, an EGFR tyrosine kinase inhibitor being investigated for treatment of non-small-cell lung cancer; LDK378 (Ceritinib), a potent ALK inhibitor used in the treatment of non-small-cell lung cancer 39 ; Terfenadine (which produces the metabolite, Fexofenadine) is a second-generation antihistamine that inhibits TNF signalling and is a therapeutic against inflammatory arthritis 40 ; Fingolimod is a first-in-class sphingosine-1-phosphate receptor modulator and immunosuppressant that is approved for the treatment of relapsing-remitting multiple sclerosis 41 ; AZD-9291 (Osimertinib), is a mutant-selective EGFR inhibitor used to treat non-small-cell lung cancer 42 and, Benserazide is a peripheral decarboxylase inhibitor that increases the amount of levodopa crossing into the brain and its subsequent conversion to dopamine, and is used in combination with other drugs in the treatment of Parkinson’s disease. We propose that these 10 compounds are candidates for repurposing in the treatment of fibrosis.…”

Identification of Disease-Associated Cryptococcal Proteins Reactive With Serum IgG From Cryptococcal Meningitis Patients

“…Cases of CM have also been reported in immunocompetent persons (9), and in persons with increased M2 polarization of brain macrophages (10). Additionally, several case reports describe CM or other forms of disseminated cryptococcal disease in persons with humoral immunity defects like immunoglobulin (Ig)G-deficiencies (11)(12)(13)(14) or X-linked hyper-IgM syndrome, which is characterized by reduced IgG and IgA serum levels and normal or elevated serum IgM (15)(16)(17)(18). CM has also been found in patients with reduced percentage of IgMproducing memory B cells (19), indicating the contribution of humoral immunity in anti-cryptococcal defense for control of C. neoformans.…”

“…Nevertheless, several studies indicate importance of humoral immunity for protection from infection (29,30). In addition to defects in B cells and antibody-mediated immunity constituting a risk factor for cryptococcal disease in humans (11)(12)(13)(14)(15)(16)(17), mice lacking B-1a B cells (31,32), or soluble IgM antibodies (33) showed significantly higher fungal burden and decreased survival upon cryptococcal challenge. Anticryptococcal antibodies produced by humans (34,35) and mice (36)(37)(38)(39) were shown to act as opsonins and promote phagocytosis and killing of cryptococcal cells in vitro.…”