In the present study, we analyzed 56 patients with non-HIV pulmonary cryptococcosis and evaluated the clinical characteristics depending on the CKD severity. We identified that the rates of disseminated cryptococcosis and non-recovery after treatment were significantly higher in patients with declined eGFR than in those with preserved eGFR. For the clinical features, fever, pleural effusion, high white blood cell count and CRP, and low level of albumin were more frequently seen in patients with declined eGFR than in those with preserved eGFR. To our best knowledge, this was the first report to clarify the clinical manifestations of severe CKD in patients with non-HIV pulmonary cryptococcosis.
CKD is one of the risk factors for pulmonary cryptococcosis; this statement is supported by several individual cases of severe clinical manifestations, such as dissemination and mortality, in chronic renal failure, especially when under dialysis (14, 20). Pyrgos V et al reported that patients hospitalized for cryptococcus meningitis had significantly more frequent comorbidities of acute (28.5%) and chronic renal failure (14.3%), compared with those in all hospitalized patients (24). Moreover, Hung MS et al identified that fever and pleural effusion were significantly more frequent in disseminated pulmonary cryptococcosis than in localized pulmonary cryptococcosis (8). Similarly, our findings showed higher rates of disseminated cryptococcosis and non-recovery after treatment in severe CKD patients with pulmonary cryptococcosis complicated by fever and pleural effusion.
The mechanisms of the association between CKD severity and the risk for pulmonary cryptococcosis remain unclear. However, some possible mechanisms, particularly the effect of the T cell response on the risk for pulmonary cryptococcosis and the pathophysiology of CKD, had been reported. HIV, which is characterized by a decline in CD4+ T cells, is one of the major causes of cryptococcosis (25). Moreover, the clinical characteristics and outcome of pulmonary cryptococcosis in patients with immunocompromising conditions, such as underlying malignancy, immunosuppressive drug use, and diabetes mellitus, were reported to be different from those in immunocompetent patients (12, 13, 23). Likewise, CKD has been associated with inactivation of the T cell response and induction of T cell apoptosis (26, 27), which causes immune dysfunction and increases the risk for infection (18, 19). Notably, host response to cryptococcal infection involves helper T cell response with production of cytokines, including tumor necrosis factor, interferon-ɤ, and interleukin-2 (28, 29). According to these data, we considered that the immune dysfunction in severe CKD might have affected the clinical characteristics and outcomes of patients with pulmonary cryptococcosis.
The clinical characteristics, including symptoms, laboratory abnormalities, and radiologic features, in pulmonary cryptococcosis are variable (30). Consistent with our results, the absence of symptoms was reported to be relatively frequent in immunocompetent patients, whereas the pulmonary cryptococcosis-associated symptoms, especially fever and chest pain, were markedly seen in immunocompromised host (12, 31). The radiologic patterns and distribution in pulmonary cryptococcosis have been closely related with host immunity. Nodules have been more frequently observed in immunocompetent patients, whereas pleural effusion, cavitation, and consolidation in a large lung area have been markedly observed in immunocompromised patients (31–34). Our results of more frequent pulmonary CT abnormalities that were limited to 1 lobe and in a unilateral lung field in patients with preserved eGFR than in those with declined eGFR supported these previous data and the involvement of immunodeficiency from CKD. In addition, we clarified that high white blood cell count and CRP and low albumin might be biomarkers for risk evaluation in patients with pulmonary cryptococcosis and severe CKD.
There were 3 limitations in the present study. First, we used 45 mL/min/1.73 m2 as the cutoff between preserved and declined eGFR, based on the results of a previous study (17). However, CKD is defined as eGFR < 60 mL/min/1.73 m2 (15), and patients with mild CKD severity were included in the group with preserved eGFR; this might have influenced the results of this study. Second, treatment including the intake of antifungal drugs or surgery was elected depending on the physician’s judgment, which might affect to the clinical outcomes. Third, the present study was performed on a small number of patients at a single hospital with limited ethnic diversity. To confirm the validity of our results, multicenter prospective studies with larger number of patients should be performed.