The mortality of AIDS patients with CM in different countries ranges from 10 to 43% [9]. It has been reported that the 2-weeks mortality rate of AIDS patients with CM is 17%, and 10-weeks mortality rate can reach 34%, and the overall 1-year mortality rate is 41% [10]. Even in developed countries, with the best antifungal and ART regimen, the mortality of HIV-associated CM within 10 weeks is still 10 to 25% [11]. Increased intracranial pressure is positively correlated with CM incidence and mortality of CM, and is positively correlated with the increase of cerebrospinal fluid fungal load [4]. Early effective control of intracranial hypertension is one of the most critical determining factors for the outcome of CM patients, and for successful antifungal therapy with reduced mortality [12]. Comprehensive treatment including anti-cryptococcus agents, intracranial pressure management and ART are the key to reduce the mortality of AIDS patients with CM infections complications [13, 14].
In this study, we found that 9% mortality rate among AIDS patients with CM receiving anti-CM treatment, which is in agreement with previous literature reports worldwide. The anti-cryptococcus treatment in induction period of the patients mainly included FLU ±5-FC (44.5%), sequential FLU ±5-FC, AmB ± 5-FC (30.5%), and AmB ± 5-FC (6.3%). Most of the patients chose FLU (800-1200 mg / d) ± 5-FC (100 mg / kg.d), due to pronounced side effects of AmB and the price of liposomal AmB. It was reported that the prognosis in AIDS patients with CM receiving AmB ± 5-FC regimen may be better than other regimens, and that anti-CM regimen, FLU ±5- FC, may be an alternative for patients intolerant AmB [15]. A 10-year data-control study indicated that Chinese AIDS patients with CM receiving anti-CM regimens, FLU ±5- FC and AmB ± 5-FC, presented no statistically significant difference in CSF pressure, CSF cryptococcal number, CSF protein, CSF WBC and disease outcome [16]. Molloy et al. reported that the induction period treatment regimens of 2-weeks FLU (1200 mg/d) + 5FC (100 mg/kg.d), 1-week AmB (1 mg/kg.d) and 2-weeks AmB (1 mg/kg.d) had similar mortality rates at 2 weeks and 10 weeks for AIDS patients with CM infection [17]. In accordance to the guideline of diagnosis and treatment of cryptococcal infection of US CDC, WHO and China [8, 12, 18], whatever not less than 2 weeks, or 4 weeks, or even 10–12 weeks, induction treatment should be ended when CSF cryptococcus culture turn negative, followed by consolidation or maintenance treatment. Our study indicated that the duration of induction period treatment in the ineffective group was significantly shorter than that in the effective group (p < 0.001), highlighting the importance of adequate duration of induction period treatment in AIDS patients with CM receiving anti-CM treatment.
We also found that the age and fasting plasma glucose of the clinically ineffective group were higher, and the incidence of cerebral infarction and consciousness disorder was higher than that of the effective group. A 10-weeks follow-up study in Thailand, Uganda, South Africa and other countries indicated that age over 50, changes in mental state, high fungal burden of CSF, removal rate of cryptococcus, and peripheral blood WBC > 10 × 109/L were independently correlated with early mortality of patients with AIDS complicated with CM infection [10]. The mechanism of cerebral infarction caused by CM may be related to extensive fibrosis of the subarachnoid space caused by cryptococcus, mechanically compression of the small veins, and increased blood flow resistance [19]. However, the correlation between the level of fasting plasma glucose, the occurrence of cerebral infarction and the poor prognosis of AIDS patients with CM infection complications has not been previously reported.
The increase of intracranial pressure is positively correlated with the morbidity and mortality of CM [4]. Increased intracranial pressure is a prerequisite for the formation of cerebral hernia, which occurs when intracranial pressure is unevenly distributed. Cerebral hernia itself has a very poor prognosis, high mortality and disability rate. Consciousness disorder is an independent risk factor for death in CM patients [5]. Lofgren et al. proposed that changes in mental state of CM patients lead to poor prognosis, and the change in mental state may be more related to the host immune response than the cryptococcus burden [20]. In this study, we found that occurrence of cerebral hernia and consciousness disorder are risk factors for the poor prognosis of AIDS patients with CM, which was consistent with conclusions reported in previous literature.
In this study, we found that the duration of treatment in the induction period is a protective factor for better prognosis of AIDS patients with CM, which is rarely reported at home and abroad. Considering the difficulty of CM treatment, the high fatality rate, the long course of disease, and that CM clearance rate in CSF is significantly related to early-stage mortality; and that the end of the induction period treatment is based on the CSF cryptococcus culture negative conversion; our study suggests that efficient anticryptococcal therapy for a sufficient induction period is especially critical to improve disease prognosis.
Another important finding of this study is that the prognosis of patients receiving shunt decompression treatment is better than that of patients without shunt treatment. Despite severe immunodeficiency and persistent CNS cryptococcus infection, AIDS and CM patients with increased intracranial pressure have indication for LP and/ or VP shunts [21]. Shunt surgery is usually a sustainable way to relieve the symptoms associated with increased intracranial pressure [22]. Baddley et al. [23] reported that shunt surgery may improve the prognosis associated with increased intracranial pressure in CM, which was consistent with our results.
This study is a clinical retrospective study. Due to limited access of follow-up data from participating patients, the impact of the clinical factors here analyzed on long-term prognosis was unattainable, and the collected ART data could not be evaluated. Additionally, the personalized choice of treatment options during the induction period lead to a biased distribution of treatment options, which limited the reliability of the conclusions obtained in terms of treatment timing/course of disease and treatment options. Future studies should address this limitations with more extensive and balanced cohorts.