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Cryptococcus: Emerging host risk factors for infection

Citation: Antonia AL, Alspaugh JA (2025) Cryptococcus: Emerging host risk factors for infection. PLoS Pathog 21(11): e1013602. https://doi.org/10.1371/journal.ppat.1013602

Editor: Mary Ann Jabra-Rizk, University of Maryland, Baltimore, UNITED STATES OF AMERICA

Published: November 5, 2025

Copyright: © 2025 Antonia, Alspaugh. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by grant funding from the National Institutes of Health: R01 AI175711 (JAA) and the Tri-Institutional Molecular Mycology and Pathogenesis Training Program 5T32AI052080 (ALA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Invasive cryptococcal disease is a feared complication for patients with immunodeficiencies. Historically a rare cause of human disease primarily in patients with hematologic malignancies, Cryptococcus neoformans became a significant cause of life-threatening opportunistic infections during the HIV pandemic [1]. C. neoformans typically establishes primary infection in the lungs, and it can disseminate to other sites with devastating complications, such as cryptococcal meningitis [2]. Globally, invasive Cryptococcus infections result in an estimated 152,000 cases of meningitis and 112,000 deaths annually, primarily in HIV positive individuals [3]. However, there is growing appreciation for invasive Cryptococcus spp. infection among non-HIV infected hosts (studies with published statistically significant associations between Cryptococcus spp. infection and comorbid conditions are summarized in Table 1 and Fig 1) [4–21]. These demonstrate that non-HIV infected hosts often have worse outcomes including higher mortality. However, several features of these studies, including varied case definitions of cryptococcosis often relying on hospital billing codes rather than direct microbiologic evidence and heterogenous study designs relying on retrospective analyses, limit the ability to make broad estimates of absolute or relative risk of invasive cryptococcosis in HIV negative patients.

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Table 1. Summary of risk factors for invasive cryptococcosis in non-HIV hosts. Studies assessing risk factors for Cryptococcus neoformans with at least >40% of study population being HIV negative. Statistically significant positive associations with comorbid disease states are denoted in blue.

https://doi.org/10.1371/journal.ppat.1013602.t001

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Fig 1. Risk factors for invasive cryptococcosis in non-HIV-infected hosts.

Multiple retrospective studies have identified hepatic, renal, pulmonary, and hematopoietic dysfunction as associated with increased risk of Cryptococcus infection. Beyond specific organ dysfunction, there is growing appreciation for the role of host genetics, metabolic derangements, iatrogenic immunosuppression, and dysregulated immune response increasing cryptococcosis risk. Created in BioRender. Antonia, A. (2025) https://BioRender.com/rtkbe07.

https://doi.org/10.1371/journal.ppat.1013602.g001

Nonetheless, there are co-morbid diseases that have been associated with the risk of cryptococcosis in multiple independent studies (Table 1). Increasing reports of invasive fungal disease in individuals without traditional risk factors emphasizes the need to understand how emerging host conditions, which are not overly immunocompromising, such as chronic metabolic disorders, influence outcomes of host-pathogen interactions. Interestingly, pathogen-specific risk factors are also potentially changing. For example, infections due to other related Cryptococcus spp. such as C. gattii have a propensity to cause life-threatening disease in apparently immunologically normal individuals (see Box 1 for further discussion of pathogen diversity as a risk for disease). This review highlights how the changing human epidemiology of invasive cryptococcosis informs our understanding of host-specific risk for infections and presents opportunities to better understand the immune response to fungal challenges.

Hematologic malignancy

Hematologic malignancy represents a broad class of diseases with diverse etiologies and treatments, where risk of opportunistic infections can arise from either the malignancy or treatment. Epidemiologic studies of cryptococcal infections in non-HIV and non-transplant hosts consistently identify hematologic malignancies as risk factors for invasive cryptococcal disease. However, these have been underpowered to identify specific syndromes associated with increased risk of invasive cryptococcosis. Additionally, guidelines from the American Society of Clinical Oncology and Infectious Diseases Society of America recommend azole-based primary anti-fungal prophylaxis for patients at risk for prolonged neutropenia. These recommendations have resulted in a reduction in the incidence of invasive fungal infections including cryptococcosis [22]. Within these limitations, a literature review from 1970 to 2014 found a disproportionate enrichment of cryptococcosis among patients with non-Hodgkins lymphoma and chronic lymphocytic leukemia [23], perhaps due to underlying immune cell dysfunction or a consequence of cytotoxic chemotherapy. Future prospective studies are needed to address whether distinct hematologic malignancies associated with perturbations in protective anti-cryptococcal immune responses are associated with clinical infection.

In addition to impaired immunity related to primary disease, the treatments for hematologic malignancies frequently lead to iatrogenic immune deficiency. In the extreme, hematopoietic stem cell transplantation results in a profound state of immune deficiency. In addition, high-dose and prolonged corticosteroid use are associated with invasive cryptococcosis [24]. Further, new therapies, including small molecules, monoclonal antibodies, and antibody-drug conjugates, are being developed that can target specific dysregulated immune signaling pathways in these cancers. Additionally, chimeric antigen receptor T-cell (CAR T-cell) therapy is increasingly used to target hematologic malignancies that are recalcitrant to standard therapies. Although no specific studies have been published to date regarding associations between this therapy and cryptococcosis, investigators are exploring using CAR T-cells directed against cryptococcal capsule antigens as a novel way to treat this life-threatening infection [25]. With the advent of these targeted therapies, a shift in our framework for thinking about general risk of infection is warranted. While perhaps not as globally immunosuppressive as general cytotoxic therapies, there are well-described but nuanced associations between specific immunomodulators and narrower subsets of infections. For example, the Bruton’s Tyrosine Kinase Inhibitor, ibrutinib, has been reported to be associated with several invasive fungal infections including aspergillosis and cryptococcosis [26]. Other small molecule kinase inhibitors such as ruxolitinib (a Janus-activated Kinase inhibitor) have been associated with increased incidence of cryptococcosis. Additionally, sorafenib (MAP Kinase inhibitor) and fostamatinib (Syk inhibitor) have been associated with infections due to other fungal pathogens [27,28]. As use of novel immune-based therapies increases, it will be important to proactively identify emerging associations between specific immune-modulating agents and invasive fungal infections to develop opportunities for prophylaxis, early diagnosis, and rapid treatment.

Solid organ transplantation

Solid organ transplant patients are maintained on immunosuppressive medications to reduce the risk of organ rejection. This immunosuppression also leads to an increased risk of infection. Among solid organ transplant recipients, cryptococcosis is the third most common invasive fungal infection [29] and is associated with increased mortality compared to HIV-infected populations [5]. Estimates of annual incidence of cryptococcal infection after solid organ transplant range from 0.2% to 5.0% [29–33]. Infection typically occurs 1–2 years after transplantation, consistent with new environmental exposure or reactivation rather than donor-derived infection [29,31,32]. The contribution of specific organ transplant type to the risk for cryptococcal disease remains unclear, as different studies have reported varied associations with incidence of cryptococcosis with kidney [33], heart [30], small bowel [30], and lung transplant [32]. These observations of widely variable infections likely reflect heterogeneity in immunosuppressive regimens and complications of failed transplant. For example, the net-state of immunosuppression required to avoid immune-mediated organ rejection contributes to overall risk of infection. On the other hand, specific therapies such as maintenance immunosuppression with calcineurin inhibitors can be associated with decreased mortality from cryptococcus infection in part due to anti-fungal activity of these compounds in addition to modulation of inflammatory response [34], emphasizing the challenges and opportunities from designing therapeutics in eukaryotic pathogens. Additionally, observations of increased mortality from cryptococcal infection in the setting of liver and renal transplantation may also reflect dysfunction of the underlying organ system (see further discussion below) [30,34]. As the total population of transplant patients continues to increase [35], combining increased resolution of clinical data with detailed mechanistic studies will be paramount to understand who is at risk for infection and inform novel therapeutic and prevention strategies.

Primary immune deficiency and host genetic susceptibility

A diverse set of primary immune deficiencies places patients at risk for more frequent and severe infections including invasive fungal infections [36]. C. neoformans infection has been described in disorders that affect both the innate and adaptive immune system such as severe combined immunodeficiency (SCID) [37], hyper IgE syndrome [38], hyper IgM syndrome [39], and idiopathic CD4 lymphopenia [40]. Additionally, the observation of invasive cryptococcal disease in patients with apparently normal immune systems spurred investigations into potential novel mechanisms of immune deficiencies.

Advances in our ability to immunophenotype patients without known risk factors for invasive fungal infections has demonstrated differences in cytokine production, baseline T-cell populations, and auto-antibodies reactive against key immune signaling pathways [41]. For example, auto-antibodies to cytokines such as interferon-γ and granulocyte-macrophage colony stimulating factor (GM-CSF) have been observed in patients with invasive cryptococcosis and no other identifiable immune deficiency [21,42]. Retrospective observational [43] and cohort studies have reported anti-GM-CSF antibodies in up to 8.1% of HIV-noninfected patients with cryptococcal meningitis. Further, anti-GM-CSF antibodies are associated with differences in Cryptococcus species, disease phenotype, and mortality [42]. New case reports of anti-GM-CSF antibodies in the context of other opportunistic pathogens emphasize a continued role for C. neoformans as a model system for interrogating host immunity [44].

Advances in human genetics have also enabled discoveries into previously unrecognized host susceptibility to invasive cryptococcal disease [45]. Due to the limited sample size of invasive cryptococcal disease in non-HIV hosts, no unbiased genome wide association studies in this population have been conducted. Nonetheless, hypothesis-driven studies have identified variants in genes with known protective cryptococcal immune function to be associated with poor outcomes in human disease. For example, risk of invasive cryptococcal disease has been associated with variants involved in both indirect pathogen sensing through FCγ receptors [46,47] or direct pathogen sensing through pattern recognition receptors including mannose-binding lectin 2 [48], dectin-2 [49], and toll-like receptors [50]. The only genome-wide association study for cryptococcosis was conducted in HIV-infected patients and identified the single-nucleotide polymorphism (SNP) rs1999713 upstream of the gene encoding the cytokine macrophage colony-stimulating factor (M-CSF). M-CSF, a structurally related cytokine to GM-CSF but with distinct immune signaling, was also differentially expressed in macrophages after stimulation with C. neoformans, and exogenous M-CSF was able to enhance macrophage phagocytosis and killing of C. neoformans [51]. As in the case of the FCγ receptor polymorphisms, this discovery in a different patient population represents an opportunity to test novel hypotheses regarding risk of cryptococcal disease in non-HIV-infected hosts.

Metabolic syndrome and hepatic dysfunction

Three diseases associated with aging and metabolic syndrome are consistently observed to have increased risk for invasive cryptococcosis in non-HIV-infected hosts: hepatic dysfunction, renal disease, and diabetes mellitus (Table 1). Additionally, despite commonalities in the mechanism of acquiring these diseases with chronic physiologic changes from metabolic syndrome, they likely have unique mechanisms of immune deficiency leading to increased susceptibility to Cryptococcus infection.

Hepatic dysfunction and cirrhosis

Liver disease is reported as a common organ dysfunction syndrome leading to invasive Cryptococcus infection (Table 1) including atypical presentations such as peritonitis [52,53] and pericarditis [54]. Further, a retrospective case-control study of 188 cases of invasive cryptococcosis identified decompensated liver cirrhosis to convey the second highest risk of cryptococcal disease after advanced HIV infection (adjusted odds ratio of 8.5) [9]. Additionally, Cryptococcus infection in patients with liver disease has repeatedly been associated with significantly higher mortality compared to similar infections in other patient populations [55,56]. While the mechanism for immune deficiency leading to increased cryptococcal disease specifically has not been identified, cirrhosis is increasingly recognized to lead to broadly dysregulated immune responses.

Diabetes mellitus

While a cryptococcal-specific mechanism of susceptibility for diabetes mellitus has not been identified, this disease is recognized to broadly lead to increased susceptibility to infectious diseases [57]. It has been demonstrated to increase risk of infection with Cryptococcus spp. in whole population level studies (Table 1) and in focused studies specifically examining patients with diabetes [58]. As a disorder of metabolic function, diabetes mellitus as a risk factor for cryptococcal disease highlights the potential role of nutritional immunity in effective fungal control. Under host-derived stress conditions, Cryptococcus neoformans upregulates numerous genes involved in nutritional regulation including of sugars, metals, and amino acids [59]. In other fungal diseases such as invasive candidiasis, elevated blood glucose has been linked to increased susceptibility to infection by increasing available energy sources for pathogens and altered host immune signaling [60]. While in the case of invasive mucormycosis, secondary metabolic changes to available iron concentrations in the context of diabetic ketoacidosis also directly contribute to pathogenesis [61]. Interestingly, recent studies of cryptococcosis in mice have shown that ketogenic diets may favor the clearance of infection in combination with antifungal therapy. These and subsequent studies will further enrich our understanding of the role of metabolism on host and microbial factors during infection [62].

Renal dysfunction

While renal homeostasis has roles in modulating local and systemic immune responses [63], there has yet to be a clearly defined mechanism that explains the increased risk of invasive cryptococcal disease with renal dysfunction (Table 1). However, patients with renal disease are more likely to die from cryptococcal infection (OR of 2.45 to 3.5) [8,13]. Further, the association between renal disease and invasive cryptococcosis has been replicated in multiple follow-up studies with specific patient populations including renal transplant patients at increased risk of cryptococcal disease acquisition, dissemination, and mortality [33,34]; and HIV-uninfected general populations without transplantation in which chronic kidney disease was associated with an increased risk of disseminated cryptococcosis and mortality [64].

Autoimmune disease and sarcoidosis

Autoimmune diseases have varied reports of increased relative prevalence of cryptococcal infection (depending on the underlying disease ranging from 5.4 times more likely up to 17 times more likely than the general population) likely reflecting the heterogenous nature of these diseases [7]. They include systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and sarcoidosis. The increased susceptibility to Cryptococcus infection certainly reflects a combination of underlying immune dysregulation, immunomodulatory treatments, and associated structural lung disease.

This combination of risk factors is illustrated by the example of sarcoidosis. In a retrospective review of all cases of cryptococcosis in France, significantly more non-HIV-infected patients were found to have sarcoidosis [65]. Of 18 patients with both sarcoidosis and cryptococcosis, 12 were receiving immunosuppressive medications including corticosteroids placing them at high risk of infection, whereas 4 had not received prior immunosuppressive medications. This demonstrates that underlying immune dysfunction or structural lung disease are risk factors independent of iatrogenic immunosuppression.

While management of sarcoidosis typically involves non-specific immunosuppression, recent reports from targeted therapies for multiple sclerosis (MS) demonstrate how novel immunomodulatory medications might unexpectedly increase risk. For example, the sphingosine-1-phosphate (S1) analog FTY720 (fingolimod) decreases central nervous system inflammation by preventing lymphocyte exit from peripheral lymphoid tissue, and by directly modulating immune signaling of effector cells [66]. Sixty patients receiving this therapy from 2006 to 2020 developed cryptococcal infection [67]. A review of 25 clinical cases identified lymphopenia as a risk factor for invasive cryptococcosis among patients on fingolimod [68], and murine studies demonstrate that fingolimod impairs macrophage function via an S1P receptor-dependent mechanism, which leads to increased reactivation of Cryptococcus infection from pulmonary granulomas [69].

Together, these studies highlight the interaction between underlying immune dysfunction, structural disease, and iatrogenic immune modulation that can contribute to C. neoformans infection risk in increasingly subtle subsets of patients with autoimmune disease.

Conclusion

Invasive cryptococcal infection in non-HIV-infected hosts is well described and associated with many adverse outcomes. As more reports become available describing cryptococcosis in this patient population, the details of under-recognized risks for fungal infections are coming into focus. It is also clear that this picture is expanding in the context of increasing transplantation, novel immunomodulatory medications, and the epidemic of chronic metabolic disorders associated with aging. With this expanding population, there will be new opportunities to better understand mechanisms by which Cryptococcus spp. cause invasive disease and therefore predict who is at risk in order to develop novel, safer modalities for treatment.

Box 1. Pathogen variation as a risk factor for invasive cryptococcosis.

Fungal genetic heterogeneity contributes to risk and variable presentation of invasive cryptococcosis. There are increasing reports of infection with the related species C. deneoformans and C. gattii; the latter of which is a more frequent cause of clinically recognized infections in non-HIV-infected populations [18]. Additionally, genome-wide association studies of Cryptococcus isolates have identified genetic variants associated with differences in fungal burden, immune recognition, and immune signaling [70,71]). While discussion of fungal genetic diversity is beyond the scope of this review, as more genetic data becomes available from clinical isolates, it is likely that pathogen genetic variation will be a key variable to explain risk and outcome of cryptococcal infection.

Box 2. Increasing complexity of host immunomodulating therapies.

Over the last several decades, there has been an increasing number of patients treated with rapidly diversifying types of immune-modulating therapies. Historically, these have been broadly immunosuppressive, such as corticosteroids and cytotoxic chemotherapy which were both individually recognized as risk for invasive fungal diseases. More recently, modulation of specific immune signaling pathways, through small molecules and monoclonal antibodies, have been less globally immunosuppressive but can still have increased susceptibility to specific subsets of pathogens depending on their unique mechanism of action. Several of these therapies, notably monoclonal antibodies that target immune checkpoints, can theoretically augment pathogen-specific immune responses. Additionally, patients are increasingly being exposed to novel combinations of these immunosuppressives. Going forward, it will be important for clinicians to be aware of new at-risk populations that emerge in this context, and when a new association arises, tackle the opportunity to learn more about invasive fungal infections.

References

  1. 1. Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev. 1995;8(4):515–48. pmid:8665468
  2. 2. Meya DB, Williamson PR. Cryptococcal disease in diverse hosts. N Engl J Med. 2024;390(17):1597–610. pmid:38692293
  3. 3. Rajasingham R, Govender NP, Jordan A, Loyse A, Shroufi A, Denning DW, et al. The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis. Lancet Infect Dis. 2022;22(12):1748–55. pmid:36049486
  4. 4. Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33(5):690–9. pmid:11477526
  5. 5. Bratton EW, El Husseini N, Chastain CA, Lee MS, Poole C, Stürmer T, et al. Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. PLoS One. 2012;7(8):e43582. pmid:22937064
  6. 6. Brizendine KD, Baddley JW, Pappas PG. Predictors of mortality and differences in clinical features among patients with Cryptococcosis according to immune status. PLoS One. 2013;8(3):e60431. pmid:23555970
  7. 7. Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997-2009. PLoS One. 2013;8(2):e56269. pmid:23457543
  8. 8. Bitar D, Lortholary O, Le Strat Y, Nicolau J, Coignard B, Tattevin P, et al. Population-based analysis of invasive fungal infections, France, 2001-2010. Emerg Infect Dis. 2014;20(7):1149–55. pmid:24960557
  9. 9. Lin Y-Y, Shiau S, Fang C-T. Risk factors for invasive Cryptococcus neoformans diseases: a case-control study. PLoS One. 2015;10(3):e0119090. pmid:25747471
  10. 10. Hevey MA, George IA, Raval K, Powderly WG, Spec A. Presentation and mortality of cryptococcal infection varies by predisposing illness: a retrospective cohort study. Am J Med. 2019;132(8):977-983.e1. pmid:31077652
  11. 11. George IA, Spec A, Powderly WG, Santos CAQ. Comparative epidemiology and outcomes of Human Immunodeficiency virus (HIV), Non-HIV non-transplant, and solid organ transplant associated cryptococcosis: a population-based study. Clin Infect Dis. 2018;66(4):608–11. pmid:29028978
  12. 12. Bhatt M, Porterfield JZ, Ribes JA, Arora V, Myint T. Changing demographics and risk factors for cryptococcosis: A 12-year review at a tertiary care centre. Mycoses. 2021;64(9):1073–82. pmid:34033158
  13. 13. Namie H, Takazono T, Hidaka Y, Morimoto S, Ito Y, Nakada N, et al. The prognostic factors for cryptococcal meningitis in non-human immunodeficiency virus patients: an observational study using nationwide database. Mycoses. 2024;67(1):e13658. pmid:37807638
  14. 14. Zhang F, Zhou Y, Tang X, Li M. Identification of risk factors for disseminated cryptococcosis in non-hiv patients: a retrospective analysis. Eur J Med Res. 2023;28(1):612. pmid:38115055
  15. 15. Coussement J, Heath CH, Roberts MB, Lane RJ, Spelman T, Smibert OC, et al. Current epidemiology and clinical features of cryptococcus infection in patients without human immunodeficiency virus: a multicenter study in 46 hospitals in Australia and New Zealand. Clin Infect Dis. 2023;77(7):976–86. pmid:37235212
  16. 16. Chau TT, Mai NH, Phu NH, Nghia HD, Chuong LV, Sinh DX, et al. A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease. BMC Infect Dis. 2010;10:199. pmid:20618932
  17. 17. Li Z, Liu Y, Cao H, Huang S, Long M. Epidemiology and clinical characteristics of cryptococcal meningitis in China (1981-2013): a review of the literature. Med Mycol Open Access. 2017;03(01).
  18. 18. Baddley JW, Chen SC-A, Huisingh C, Benedict K, DeBess EE, Galanis E, et al. MSG07: an international cohort study comparing epidemiology and outcomes of patients with Cryptococcus neoformans or cryptococcus gattii infections. Clin Infect Dis. 2021;73(7):1133–41. pmid:33772538
  19. 19. Lui G, Lee N, Ip M, Choi KW, Tso YK, Lam E, et al. Cryptococcosis in apparently immunocompetent patients. QJM. 2006;99(3):143–51. pmid:16504989
  20. 20. Yuchong C, Fubin C, Jianghan C, Fenglian W, Nan X, Minghui Y, et al. Cryptococcosis in China (1985-2010): review of cases from Chinese database. Mycopathologia. 2012;173(5–6):329–35. pmid:21979866
  21. 21. Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med. 2012;367(8):725–34. pmid:22913682
  22. 22. Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36(30):3043–54. pmid:30179565
  23. 23. Schmalzle SA, Buchwald UK, Gilliam BL, Riedel DJ. Cryptococcus neoformans infection in malignancy. Mycoses. 2016;59(9):542–52. pmid:26932366
  24. 24. Lewis RE, Cahyame-Zuniga L, Leventakos K, Chamilos G, Ben-Ami R, Tamboli P, et al. Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study. Mycoses. 2013;56(6):638–45. pmid:23551865
  25. 25. Machado MP, Dos Santos MH, Guimarães JG, de Campos GY, Oliveira Brito PKM, Ferreira CMG, et al. GXMR-CAR containing distinct GXM-specific single-chain variable fragment (scFv) mediated the cell activation against Cryptococcus spp. And had difference in the strength of tonic signaling. Bioengineered. 2023;14(1):2281059. pmid:37978838
  26. 26. Messina JA, Giamberardino CD, Tenor JL, Toffaletti DL, Schell WA, Asfaw YG, et al. Susceptibility to cryptococcus neoformans infection with bruton’s tyrosine kinase inhibition. Infect Immun. 2023;91(8):e0004223. pmid:37404186
  27. 27. Tsukui D, Fujita H, Suzuki K, Hirata K. A case report of cryptococcal meningitis associated with ruxolitinib. Medicine (Baltimore). 2020;99(13):e19587. pmid:32221077
  28. 28. Zarakas MA, Desai JV, Chamilos G, Lionakis MS. Fungal infections with ibrutinib and other small-molecule kinase inhibitors. Curr Fungal Infect Rep. 2019;13(3):86–98. pmid:31555394
  29. 29. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–11. pmid:20218876
  30. 30. Wu G, Vilchez RA, Eidelman B, Fung J, Kormos R, Kusne S. Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis. 2002;4(4):183–8. pmid:12535260
  31. 31. Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis. 2001;7(3):375–81. pmid:11384512
  32. 32. George IA, Santos CAQ, Olsen MA, Powderly WG. Epidemiology of cryptococcosis and cryptococcal meningitis in a large retrospective cohort of patients after solid organ transplantation. Open Forum Infect Dis. 2017;4(1):ofx004. pmid:28480277
  33. 33. Gassiep I, McDougall D, Douglas J, Francis R, Playford EG. Cryptococcal infections in solid organ transplant recipients over a 15-year period at a state transplant center. Transpl Infect Dis. 2017;19(1):10.1111/tid.12639. pmid:27875016
  34. 34. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, et al. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality. J Infect Dis. 2007;195(5):756–64. pmid:17262720
  35. 35. Global Observatory on Donation and Transplantation (GODT). Organ Donation and Transplantation Activities 2023 Report. Available from: https://www.transplant-observatory.org/wp-content/uploads/2024/12/2023-data-global-report-17122024.pdf
    • 36. Lanternier F, Cypowyj S, Picard C, Bustamante J, Lortholary O, Casanova J-L, et al. Primary immunodeficiencies underlying fungal infections. Curr Opin Pediatr. 2013;25(6):736–47. pmid:24240293
    • 37. Alsum Z, Al-Saud B, Al-Ghonaium A, Bin Hussain I, Alsmadi O, Al-Mousa H, et al. Disseminated cryptococcal infection in patient with novel JAK3 mutation severe combined immunodeficiency, with resolution after stem cell transplantation. Pediatr Infect Dis J. 2012;31(2):204–6. pmid:22138680
    • 38. Jacobs DH, Macher AM, Handler R, Bennett JE, Collen MJ, Gallin JI. Esophageal cryptococcosis in a patient with the hyperimmunoglobulin E-recurrent infection (Job’s) syndrome. Gastroenterology. 1984;87(1):201–3. pmid:6373479
    • 39. Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003;82(6):373–84. pmid:14663287
    • 40. Ahmad DS, Esmadi M, Steinmann WC. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med. 2013;3(2):37–47. pmid:23930241
    • 41. Townsend K, Kannambath S, Hayman G, Doffinger R, Ceron-Gutierrez L, Ebrahimi S, et al. Immunophenotyping of apparently immunocompetent hosts with cryptococcosis reveals IL-17 deficiency as a unifying susceptibility factor. Clin Exp Immunol. 2025;:uxaf053. pmid:40856059
    • 42. Jiang Y-K, Zhou L-H, Cheng J-H, Zhu J-H, Luo Y, Li L, et al. Anti-GM-CSF autoantibodies predict outcome of cryptococcal meningitis in patients not infected with HIV: A cohort study. Clin Microbiol Infect. 2024;30(5):660–5. pmid:38295989
    • 43. Rosen LB, Freeman AF, Yang LM, Jutivorakool K, Olivier KN, Angkasekwinai N, et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J Immunol. 2013;190(8):3959–66. pmid:23509356
    • 44. Lee E, Miller C, Ataya A, Wang T. Opportunistic infection associated with elevated GM-CSF autoantibodies: a case series and review of the literature. Open Forum Infect Dis. 2022;9(5):ofac146. pmid:35531378
    • 45. Onyishi CU, May RC. Human immune polymorphisms associated with the risk of cryptococcal disease. Immunology. 2022;165(2):143–57. pmid:34716931
    • 46. Hu X-P, Wu J-Q, Zhu L-P, Wang X, Xu B, Wang R-Y, et al. Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients. PLoS One. 2012;7(8):e42439. pmid:22879986
    • 47. Meletiadis J, Walsh TJ, Choi EH, Pappas PG, Ennis D, Douglas J, et al. Study of common functional genetic polymorphisms of FCGR2A, 3A and 3B genes and the risk for cryptococcosis in HIV-uninfected patients. Med Mycol. 2007;45(6):513–8. pmid:17710620
    • 48. Ou X-T, Wu J-Q, Zhu L-P, Guan M, Xu B, Hu X-P, et al. Genotypes coding for mannose-binding lectin deficiency correlated with cryptococcal meningitis in HIV-uninfected Chinese patients. J Infect Dis. 2011;203(11):1686–91. pmid:21592999
    • 49. Hu X-P, Wang R-Y, Wang X, Cao Y-H, Chen Y-Q, Zhao H-Z, et al. Dectin-2 polymorphism associated with pulmonary cryptococcosis in HIV-uninfected Chinese patients. Med Mycol. 2015;53(8):810–6. pmid:26129889
    • 50. Jiang Y-K, Wu J-Q, Zhao H-Z, Wang X, Wang R-Y, Zhou L-H, et al. Genetic influence of Toll-like receptors on non-HIV cryptococcal meningitis: An observational cohort study. EBioMedicine. 2018;37:401–9.
    • 51. Kannambath S, Jarvis JN, Wake RM, Longley N, Loyse A, Matzaraki V, et al. Genome-wide association study identifies novel colony stimulating factor 1 locus conferring susceptibility to cryptococcosis in human immunodeficiency virus-infected South Africans. Open Forum Infect Dis. 2020;7(11):ofaa489. pmid:33269293
    • 52. Park WB, Choe YJ, Lee K-D, Lee CS, Kim HB, Kim NJ, et al. Spontaneous Cryptococcal peritonitis in patients with liver cirrhosis. Am J Med. 2006;119(2):169–71. pmid:16443429
    • 53. Bal CK, Bhatia V, Khillan V, Rathor N, Saini D, Daman R, et al. Spontaneous cryptococcal peritonitis with fungemia in patients with decompensated cirrhosis: report of two cases. Indian J Crit Care Med. 2014;18(8):536–9. pmid:25136195
    • 54. Phang CR, Farooqi A, Sangwan Y. Unmasking the unusual: Cryptococcal pericarditis in a patient with liver failure - a rare occurrence. Am J Case Rep. 2024;25:e943530. pmid:39037967
    • 55. Cheng J-H, Yip C-W, Jiang Y-K, Zhou L-H, Que C-X, Luo Y, et al. Clinical predictors impacting cryptococcal dissemination and poor outcome in patients with cirrhosis. Open Forum Infect Dis. 2021;8(7):ofab296. pmid:34250196
    • 56. Zhou Q-H, Hu C-Q, Shi Y, Wu F-T, Yang Q, Guan J, et al. Cryptococcosis in patients with liver cirrhosis: Death risk factors and predictive value of prognostic models. Hepatobiliary Pancreat Dis Int. 2021;20(5):460–8. pmid:34233849
    • 57. Harding JL, Benoit SR, Gregg EW, Pavkov ME, Perreault L. Trends in rates of infections requiring hospitalization among adults with versus without diabetes in the U.S., 2000-2015. Diabetes Care. 2020;43(1):106–16. pmid:31615853
    • 58. Lao M, Li C, Li J, Chen D, Ding M, Gong Y. Opportunistic invasive fungal disease in patients with type 2 diabetes mellitus from Southern China: Clinical features and associated factors. J Diabetes Investig. 2020;11: 731–44.
    • 59. Perfect JR, Kronstad JW. Cryptococcal nutrient acquisition and pathogenesis: dining on the host. Microbiol Mol Biol Rev. 2025;89(1):e0001523. pmid:39927764
    • 60. Rodrigues CF, Rodrigues ME, Henriques M. Candida sp. infections in patients with diabetes mellitus. J Clin Med. 2019;8(1):76. pmid:30634716
    • 61. Ibrahim AS, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis. 2012;54(Suppl 1):S16-22. pmid:22247441
    • 62. Palmucci JR, Sells BE, Giamberardino CD, Toffaletti DL, Dai B, Asfaw YG, et al. A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection. mBio. 2024;15(5):e0064924. pmid:38619236
    • 63. Foresto-Neto O, Menezes-Silva L, Leite JA, Andrade-Silva M, Câmara NOS. Immunology of kidney disease. Annu Rev Immunol. 2024;42(1):207–33. pmid:38211945
    • 64. Tashiro H, Haraguchi T, Takahashi K, Sadamatsu H, Tajiri R, Takamori A, et al. Clinical impact of advanced chronic kidney disease in patients with non-HIV pulmonary cryptococcosis. BMC Pulm Med. 2020;20(1):116. pmid:32349734
    • 65. Bernard C, Maucort-Boulch D, Varron L, Charlier C, Sitbon K, Freymond N, et al. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM. 2013;106(6):523–39. pmid:23515400
    • 66. Chun J, Hartung H-P. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33(2):91–101. pmid:20061941
    • 67. Del Poeta M, Ward BJ, Greenberg B, Hemmer B, Cree BAC, Komatireddy S, et al. cryptococcal meningitis reported with fingolimod treatment: case series. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1156. pmid:35318259
    • 68. Li X, Paccoud O, Chan K-H, Yuen K-Y, Manchon R, Lanternier F, et al. Cryptococcosis associated with biologic therapy: a narrative review. Open Forum Infect Dis. 2024;11(7):ofae316. pmid:38947739
    • 69. Bryan AM, You JK, McQuiston T, Lazzarini C, Qiu Z, Sheridan B, et al. FTY720 reactivates Cryptococcal granulomas in mice through S1P receptor 3 on macrophages. J Clin Invest. 2020;130(9):4546–60. pmid:32484801
    • 70. Sephton-Clark P, Tenor JL, Toffaletti DL, Meyers N, Giamberardino C, Molloy SF, et al. Genomic variation across a clinical Cryptococcus population linked to disease outcome. mBio. 2022;13(6):e0262622. pmid:36354332
    • 71. Gerstein AC, Jackson KM, McDonald TR, Wang Y, Lueck BD, Bohjanen S, et al. Identification of pathogen genomic differences that impact human immune response and disease during Cryptococcus neoformans infection. mBio. 2019;10(4):e01440-19. pmid:31311883