Cryptococcal infection is primarily associated with HIV infection, with an annual incidence of cryptococcal meningitis ranging from 5–10% among HIV-positive patients 3. However, it is crucial to note its increasing prevalence in patients with malignancies, organ or stem cell transplantation, severe diabetes, and autoimmune diseases, leading to a rising incidence of cryptococcal infection. In China, most cryptococcal infections occur in HIV-negative patients4. Current research suggests that the susceptibility to cryptococcal infection in the healthy population in China may be associated with specific genetic factors, such as polymorphisms in genes such as FCGRIIB (Fc gamma receptors IIB) and Dectin-2, as well as gene defects in mannose-binding lectin (MBL).
The CNS and lungs are the organs most commonly affected by cryptococcosis5. In this study, patients with disseminated cryptococcosis frequently exhibited simultaneous involvement of multiple sites, with the CNS and lungs being the most prevalent, followed by the lungs and skin. Disseminated cryptococcosis carries a high mortality rate and poor prognosis. By analyzing patient information, laboratory test results, clinical manifestations, and pathological findings of patients in the PC, CM, and DC groups, our study aims to identify the risk factors for disseminated cryptococcosis. Early identification of these risk factors could guide healthcare professionals in implementing timely and proactive interventions, ultimately improving patient outcomes.
In this study, the mortality rate in the DC group was significantly higher than in the PC and CM groups. The multivariate logistic regression analysis showed that elevated plasma cytokine IL-10 levels independently contributed to disseminated cryptococcosis in both PC and CM groups.Previous studies have demonstrated that neutrophils arecritical in host defense against cryptococcal infection. Neutrophil recruitment to Cryptococcus species requires activation of the complement C5a-C5aR pathway and activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) systems, resulting in the production of pro-inflammatory cytokines, including elevated levels of IL-10 and IL-126.Furthermore, the cryptococcal polysaccharide glucuronoxylomannan promotes the secretion of IL-10 and IL-47. Moreover, IL-10 has been associated with cryptococcal evasion in several studies. A Th2 immune response to new Cryptococcus strains inducestheir virulence factors toenhance the release of IL-10. Consequently, IL-10induces a Th2 response while inhibiting the Th1 response8. Elevated levels of IL-10 have been associated with uncontrolled fungal infections9. In this study, elevated IL-10 level was identified as an independent risk factor for developing disseminated cryptococcosis.
Furthermore, studies have indicated that patients with decompensated liver cirrhosis face an increased risk of developing disseminated cryptococcosis 10.We found that decompensated liver cirrhosis is an independent risk factor for developing disseminated cryptococcosis in patients with cryptococcal meningitis. This association could be attributed to Cryptococcus species bypassing the liver’s clearance system in patients with decompensated liver cirrhosis and directly entering the systemic circulation through collateral circulation, resulting in cryptococcal sepsis and subsequent dissemination to the CNS11. Patients with decompensated liver cirrhosis have impaired innate and cell-mediated immunity, increasing the susceptibility to invasive cryptococcal disease. Moreover, the mortality risk is high with the onset of the disease 12.
This study demonstrated that decreased serum albumin level is an independent risk factor for developing disseminated cryptococcosis in the PC group. However, there is currently limited research on the correlation between disseminated cryptococcosis and decreased serum albumin. Some domestic studies have identified reduced serum albumin as an independent risk factor for extrapulmonary cryptococcal infection; however, the underlying mechanisms remain unclear13. Furthermore, a study by Yu Huang et al.14demonstrated a significant correlation between serum albumin levels and the mortality rate of cryptococcal meningitis.
In the single-factor analysis, diabetes and long-term use of immunosuppressive agents showed significant association with the dissemination of cryptococcal infection. However, the results were inconsistent in the multivariate analysis. This variation could be attributed to the limited sample size, which affects the statistical power. Research has indicated that patients with diabetes experience metabolic abnormalities and compromised immune function, creating favorable conditions for fungal growth and invasion, thereby increasing the risk of fungal infection in the human body 15. Individuals with diabetes are moresusceptible to fungal infections than healthy individuals16.Prolonged use of immunosuppressive agents weakens cellular and humoral immunity and increases the vulnerability to fungal infections. Cryptococcus species couldrapidly disseminate throughout the body via the bloodstream 17.
In addition to the factors mentioned above influencing the risk of disseminated cryptococcosis, new cryptococcal infections are commonly observed in patients on long-term glucocorticoid use, accounting for approximately one-third of HIV-negative patients18. The extended use of glucocorticoids reduces the production of pro-inflammatory cytokines and weakens the body’s ability to resist pathogenic microorganisms, thereby increasing the likelihood of fungal infections19. Eosinophils contribute to the body's defense against fungal infections, especially by clearing fungi from the lungs. They are commonly associated with toxic mediator release and phagocytic activity20.
The CT manifestations of pulmonary cryptococcal infections vary widely. Asymptomatic individuals frequently present with nodular or mass-like lesions on chest CT scans, whereas immunocompromised patients typically display pneumonia-like or mixed patterns21. Consistent with these findings, the PC group in our study predominantly exhibited a unilateral lung nodule or a pattern resembling a mass (52.6%), whereas the DC group presented with patchy bilateral opacities or ground-glass infiltrates (59.3%). In addition to these imaging findings, pulmonary cryptococcal infections can present with halo signs, pleural effusion, cavitation, pleural thickening, and bronchial inflation signs.
In summary, Cryptococcus species potentially invade various tissues and organs in the human body, posing a significant health threat. Pulmonary cryptococcosis is the most prevalent form, characterized by a fungal infection of the respiratory system resulting from inhalation of cryptococcal spores. Cryptococcal infections can spread from the lungs to the CNS and other extrapulmonary sites. With the continuous evolution of Cryptococcus species and an increasingly susceptible population, disseminated cryptococcosis casesareincreasing. In our study, the PC group exhibited a more favorable prognosisthan the CM and DC groups, with the highest mortality rate observed in the DC group, followed by the CM group. Elevated IL-10 level was identified as an independent risk factor for disseminated cryptococcosis in both the PC and CM groups. In contrast, decompensated liver cirrhosis was identified as an independent risk factor for disseminated cryptococcosis in the CM group. Decreased serum albumin level was identified as an independent risk factor for disseminated cryptococcosis in the PC group. Therefore, patients with disseminated cryptococcosis must remain highly vigilant.