In this study, we retrospectively analyzed the clinical features of 8 patients with cryptococcemia. This is a rare blood stream infection. It is a first study of cryptococcemia reported in north China as we know by now. It is consistent with the phenomenon that the incidence of cryptococcosis in north China is less than which in south China[4–6]. The study showed the characterization of patients in whom cryptococcemia was the initial diagnostic proof of cryptococcosis. Meanwhile, it also provided information about the microbial features of Cryptococcus spp. isolated from blood.
As a sign of graveness, cryptococcemia was mostly developed in immunocompromised hosts especially in patients with late-stage HIV infection[1]. In addition to HIV infection, solid-organ transplantation, immunosuppressive medications treatment, chronic renal failure, hematologic malignancy, severe hepatic diseases and rheumatologic disorders can also predispose individuals to this infection[1–3]. In our study, 87.5% of patients had predisposing conditions. 6 patients (75%) had been treated with corticosteroids or immunosuppressants for various reasons before identification of cryptococcal infection. It was noteworthy that 1 cryptococcemia patient with viral myocarditis was apparently immunocompetent in this study. The potential of Cryptococcus spp. to cause endovascular infection and endocarditis is very low. Interestingly, cryptococcosis occurs more frequently in immunocompetent patients than in immunocompromised patients in China[7–10]. The mechanism of this is not clear. Maybe there are immune function abnormalities in this kind of patients that cannot be recognized by laboratory tests at present. It is worth mentioning that this patient suffered multiple deep vein catheterization, which does not exclude the probability of iatrogenic bloodstream infection. In addition, it is worth noting that Cryptococcus is known to be common in excreta from certain birds such as pigeons. All patients in our study had no history of pigeon contact. Many clinicians only consider the diagnosis of cryptococcosis based the contact history with pigeons, which greatly delayed the diagnosis of cryptococcosis.
The symptoms of cryptococcemia were usually nonspecific and atypical. They were sometimes mistaken for manifestations of primary disease. These posed considerable diagnostic challenges for clinicians. Fever were found in all eight patients with cryptococcemia. Due to the unique propensity of CNS invasion of Cryptococcus, approximately 80% of cryptococcemia patients had complicated meningitis[1, 11]. Clinical manifestations of CNS involvement include headache, nausea/vomiting, altered consciousness and signs of meningeal irritation. In this study most (75%, 6/8) patients lacked typical symptoms of headache and nausea/vomiting. 4 (50%, 4/8) patients presented subtle confusion. The mild symptoms of headache and nausea/vomiting may be ignored in medical daily inquiring or not described in the medical record. Therefore, the incidence of symptoms of meningitis was likely to be underestimated.
The imaging manifestations in early stage of cryptococcal meningitis were not obvious. MRI/CT scan of the brain were performed in 4 patients in our study. None showed evidence of cryptococcal infection. So negative brain imaging cannot preclude the development of disseminated cryptococcal infection. Rather than imaging examination, the test of cryptococcal polysaccharide capsular antigen (CrAg) in serum or CSF is highly sensitive and specific for disseminated Cryptococcus infection[12]. It is an early diagnosis method of cryptococcosis. And it took less time than blood culture of Cryptococcus (mean time, 7.5 days in this study). With the introduction of the point-of-care lateral flow cryptococcal antigen assay, it has been greatly facilitated with lower cost and more sensitivity than earlier serological tests[13, 14]. However, it was regret that serum cryptococcal antigen assay were not performed in most patients. So the diagnosis of opportunistic infections including cryptococcosis should be early considered in immunocompromised patients. It may be necessary to perform serum cryptococcal antigen test in routine diagnostic work-up in high risk individuals especially with fever of unknown origin.
C. neoformans and C. gattii are the two main pathogenic cryptococcal species for humans[14]. 11 Cryptococcus spp. isolates are all C. neoformans var. grubii. The data were consistent with a multicenter investigation that C. neoformans var. grubii accounted for 97.1% of all C. neoformans species complex in China[15]. 11 clinical strains of Cryptococcus were sensitive to fluconazole, voriconazole, itraconazole, amphotericin B and flucytosine in vitro. The results provided some information about the microbial features of Cryptococcus spp. isolated from blood. However, it is difficult to draw conclusions about the overall microbiology and antifungal drug sensitivity because of its small sample size.
Cryptococcemia is an extremely severe form of invasive cryptococcosis with poor prognosis. It had shown a high mortality rate between 30% and 40% in previous studies[1, 2, 16]. Effective antifungal therapy is the cornerstone to treat disseminated cryptococcosis including cryptococcemia. It was recommended that induction therapy for disseminated cryptococcosis using fungicidal regimens, such as a polyene and flucytosine, followed by consolidation and maintenance therapy using suppressive regimens with fluconazole[17]. The other triazoles including itraconazole, voriconazole and posaconazole are active against cryptococcal isolates in vitro but due to the differences in bioavailability, CSF permeability, drug interactions, cost-benefit ratio, and lack of strong studies on cryptococcosis, these agents were not recommended as first-line agents for consolidation or maintenance therapy. They were used clinically in salvage situations. While echinocandins have no in vivo activity versus Cryptococcus species. In our study, 6 patients received antifungal treatment. But only 1 patient received amphotericin B-containing regimen and flucytosine-containing regimen, respectively. Most patients didn’t receive appropriate antifungal therapy. Most clinicians agreed that voriconazole was an effective treatment for cryptococcosis while neglected the fact that it was not enough in the treatment of disseminated cryptococcosis. In addition, considerable clinicians preferred conservative regimens rather than concerned about the side effects of amphotericin B and flucytosine. Both of above causes led to the inadequacy of early induction treatment of the disease.
Although cryptococcemia may have contributed to the fatal outcome of itself, we believe that the delay in the diagnosis and improper treatment is the main contributing factor. The patients first diagnosed by blood cultures had mild and neglected symptoms of meningitis, which may lead to the delayed diagnosis. These patients also had less access to effective antifungal treatment. It caused poor outcome. This report highlighted the need to early identify this rare infectious disease and its clinical presentations, especially in immunocompromised patients. The results further highlighted the important of prompt aggressive interventions in improving outcome of cryptococcemia. However, the research has several limitations. Although we collected 10-year data of cryptococcemia in PLAGH, the sample size of this research is still small due to the low incidence of cryptococcemia. Another limitation is the absent usage of latex agglutination and lateral-flow assay for CrAg determination. Furthermore, the antifungal susceptibility of Cryptococcus may vary among different hospitals, especially those in different regions. Therefore, prospective studies involving larger sample size and more hospitals are needed to provide more information about cryptococcemia.