Cryptococcosis is an opportunistic fungal infection caused by Cryptococcus species, contributing to approximately 180,000 deaths annually worldwide (Dao et al., 2024). The World Health Organization has designated Cryptococcus as a critical priority pathogen. Among Cryptococcus species, only Cryptococcus neoformans (C. neoformans) and Cryptococcus gattii (C. gattii) are recognized as human pathogens, with C. neoformans causing approximately 95% of infections and C. gattii accounting for the remaining cases. The epidemiology of cryptococcosis demonstrates distinct patterns based on host immune status. C. neoformans predominantly affects immunocompromised individuals. Beyond HIV-infected patients and those with malignancies, recipients of systemic immunosuppressive therapy–including solid organ transplant recipients and patients with autoimmune disorders–constitute a significant high-risk population (Ding et al., 2017; Chang et al., 2024). Studies confirm that glucocorticoids, tumor necrosis factor-α (TNF-α) inhibitors, and calcineurin inhibitors substantially impair Th1-type immune responses and macrophage-mediated clearance, thereby significantly elevating the risk of cryptococcal infection (Meya and Williamson, 2024).

The pathogenic pathway begins with inhalation of fungal particles through the respiratory tract, leading to primary pulmonary infection. The organism's remarkable ability to survive within phagocytic cells is mediated by key virulence factors such as capsular polysaccharides, phospholipases, and ureases. Through sophisticated mechanisms including the "Trojan horse" strategy, Cryptococcus can disseminate from the lungs to various organ systems. The central nervous system (CNS) is the most commonly affected extrapulmonary site, though the infection may also involve the skin, lymph nodes, and bone tissue (Denham and Brown, 2018). Clinical presentation shows considerable variation depending on host immune status, with immunocompromised patients being particularly vulnerable to disseminated disease. Immunosuppressive therapy exacerbates this vulnerability. For example, glucocorticoids directly impair the secretion of interferon-γ (IFN-γ) by alveolar macrophages, thereby hindering the host's ability to eliminate cryptococcal pathogens via phagocytic clearance mechanisms (Rohatgi and Pirofski, 2015).

Myasthenia gravis (MG) is an autoimmune disease mediated by anti-acetylcholine receptor antibodies, which impair neuromuscular transmission and cause fatigable weakness. Although immunosuppressive therapies (e.g., glucocorticoids and immunomodulators) routinely used in MG management typically increase susceptibility to several opportunistic infections (Zhou et al., 2021; García Estévez and Pardo Fernández, 2023), cryptococcosis in this patient population remains remarkably rare in the literature.

In this study, we report case series of three patients of cryptococcosis in MG receiving immunosuppressive therapy and provide a comprehensive review of the currently published relevant literature. Their clinical characteristics and management approaches are discussed.

Cryptococcosis poses a significant threat to immunocompromised individuals, particularly MG patients undergoing immunosuppressive therapy. Our study represents the first comprehensive literature review summarizing cases of MG complicated with cryptococcal infection. Our analysis of three new cases combined with 14 published literature reports (Jia et al., 2023; Huong et al., 2017; Shah et al., 2015; Lorenzoni et al., 2011; Takenaka et al., 2010; Yip et al., 1998; Schmidt and Padberg, 1998; Rowland et al., 1965; Narayanan et al., 2011; Ieronymaki et al., 2021; Youssef et al., 2024; Soni et al., 2020; Asif et al., 2019; Drogari-Apiranthitou et al., 2024) reveals that affected patients are typically middle-aged (50–60 years) with no gender predominance. The infection most commonly involves the CNS, followed by pulmonary and cutaneous manifestations, with approximately one-third of cases progressing to disseminated disease that invariably involves the CSF, underscoring the aggressive nature of cryptococcosis in this setting. Notably, the overwhelming majority of affected patients were receiving dual or triple immunosuppressive regimens, highlighting the delicate balance between managing MG and preventing opportunistic infections. These findings emphasize the need for heightened clinical vigilance, prompt diagnostic evaluation, and individualized treatment strategies in this vulnerable population.

The development of cryptococcosis in MG patients is multifactorial, involving both iatrogenic immunosuppression and underlying immune dysregulation. Immunosuppressive agents such as glucocorticoids, azathioprine, and tacrolimus, cornerstones of MG management, significantly impair host defenses against fungal infections. Thymectomy-associated MG, as observed in three patients of our study, represents a well-documented but incompletely understood phenomenon with reported incidence rates of 1.0%-9.1% (Kim et al., 2021), may further exacerbate immune dysfunction, though the precise mechanisms remain unclear. Potential mechanisms include postoperative immune dysregulation, persistence of autoreactive T-cell clones, or undetected subclinical autoimmune status prior to surgery (Kim et al., 2021; Mineo et al., 2018).

CD4+ T lymphocytes play a pivotal role in anti-cryptococcal immunity, primarily through their differentiation into Th1 and Th17 effector subsets. These subsets secrete critical cytokines, including interleukin-2, tumor necrosis factor-α, and interferon-gammar (IFN-γ), which orchestrate macrophage phagocytic activity and directly suppress fungal proliferation (Rohatgi and Pirofski, 2015). In our study, the gradient of disease severity of patients is correlated with CD4+ T cell depletion, mirroring findings in HIV-associated cryptococcosis. Based on a comparative analysis of these 17 clinical cases, patients with disseminated cryptococcosis exhibited significantly lower CD4+ T cell counts than those with localized cryptococcal infections. This aligns with existing evidence suggesting that CD4+ T cell counts below 400 cells/μL substantially increase the risk of disseminated cryptococcosis in non-HIV immunocompromised hosts (Denham and Brown, 2018; Wang et al., 2021).

WES analysis of our Case 1 identified a heterozygous FAS mutation (p.S19L), which plays a central role in the physiological regulation of programmed cell death. This variant linked to autoimmune lymphoproliferative syndrome (Paskiewicz et al., 2023). Such patients fail to adequately regulate immune cell populations, frequently developing aberrant lymphocyte proliferation. While potentially contributing to immune dysregulation, its specific role in cryptococcal susceptibility requires further investigation. This finding underscores our incomplete understanding of genetic-immune interactions in cryptococcosis development among MG patients. The host's defense against Cryptococcus depends critically on IFN-γ-mediated Th1 immunity, where elevated CSF IFN-γ levels correlate with better treatment outcomes in cryptococcal meningitis (Rohatgi and Pirofski, 2015; Okurut et al., 2025). Our case series showed negative anti-IFN-γ autoantibodies, which are recognized to disrupt macrophage activity and intracellular microbial killing, as demonstrated in Non-tuberculous mycobacteria and T. marneffei infections (Tang et al., 2010; Kampitak et al., 2011). More recently, anti-granulocyte-macrophage colony-stimulating factor autoantibodies have emerged as significant predictors of both cryptococcal susceptibility and poorer survival outcomes, independent of Cryptococcus species (Jiang et al., 2024; Arango-Franco et al., 2024).

Cryptococcosis in MG patients often mimic malignancies (e.g. lymphoma, metastatic malignancies) and other infections (e.g. tuberculosis) (Joo et al., 2015; Zhang et al., 2012). In our series, hypermetabolic lesions on PET-CT initially raised suspicion for metastatic thymoma or other malignancies, delaying appropriate treatment. CrAg testing proved invaluable, with 88.2% positivity among 17 MG patients. It is demonstrated that particular utility of mNGS in extrapulmonary cases (93.5% sensitivity and 96.0% specificity for CNS cryptococcosis), offering rapid species identification and aiding in the diagnosis of culture-negative infections (Gan et al., 2022). Histopathology and fungal culture remain the diagnostic gold standards, but their clinical utility is limited by the invasive nature of tissue sampling and prolonged culture duration. For example, in our Case 3, persistent pulmonary nodules despite antifungal therapy necessitated surgical resection to exclude malignancy, highlighting the diagnostic ambiguity that often accompanies cryptococcosis in immunocompromised hosts.

Infection is the most significant trigger for worsening MG (Gilhus et al., 2018). Additionally, certain antibiotics can impair neuromuscular transmission, exacerbating muscle weakness in MG patients (Gilhus et al., 2018). Managing cryptococcosis in these individuals also requires careful balancing of antifungal efficacy against the potential toxicity of immunosuppressants. Induction therapy utilizing L-Amb (with amphotericin B lipid complex or amphotericin B as alternative) and flucytosine, as recommended by current guidelines, was employed in CNS and disseminated cryptococcal infection (Chang et al., 2024). However, our Case 1 developed arrhythmias secondary to amphotericin B, necessitating a switch to fluconazole and flucytosine. TDM was critical in this patient due to fluconazole-mediated inhibition of tacrolimus metabolism, which led to supratherapeutic tacrolimus levels and potential toxicity. In our Case 3, the patient developed renal toxicity from liposomal amphotericin B and fluconazole, displayed unresponsive to other azole antifungal medications, and ultimately required surgical resection, highlighting the importance of individualized treatment strategies and close monitoring in such cases. The optimal duration of antifungal therapy remains uncertain, particularly in immunocompromised hosts. While undetectable CrAg levels may serve as a pragmatic endpoint, this approach requires validation in larger studies.

Given the limited published cases of MG with cryptococcosis, current case reports demonstrate substantial heterogeneity in both treatment regimens and the application of immunosuppressive agents. Analysis of the included patients indicates that initial treatment most commonly utilized amphotericin B-based regimens, either as monotherapy or in combination. The majority of patients achieved favorable outcomes. If localized lesions develop, a comprehensive assessment of the necessity for surgical intervention must be conducted. In such patients, immunosuppressant use serves a dual role: it constitutes one of the risk factors for cryptococcal invasion due to compromised immunity, while simultaneously functioning as a protective measure against pathological inflammatory responses during treatment (Hargarten et al., 2023). Overly rapid discontinuation of immunosuppressants may precipitate cryptococcal inflammatory syndromes. Among the included cases, only one patient developed immune reconstitution syndrome following prednisone cessation. This phenomenon may be attributed to the sustained suppression of T-cell activation and proinflammatory cytokine release by immunosuppressive therapy, thereby preventing the occurrence of excessive inflammation.

In conclusion, cryptococcosis in MG patients presents complex diagnostic and therapeutic challenges due to immune dysfunction and immunosuppressive therapy. Achieving optimal therapeutic balance between treatment of MG and cryptococcosis remains paramount in each individual case. A multidisciplinary approach combining rapid diagnostics, TDM-guided treatment adjustment, and personalized antifungal regimens is crucial. Further research is needed to optimize risk stratification and management strategies for this vulnerable population.