Potential killer: HIV-related cryptococcal meningitis.   Cryptococcosis is an opportunistic infection caused by Cryptococcus and is closely related to Acquired Immune Deficiency Syndrome (AIDS). The genus Cryptococcus includes 17 species and 18 varieties, of which Cryptococcus neoformans is the most important pathogen of this disease.

Cryptococcal meningitis (cryptococcal meningitis, CM) is an important cause of hospitalization and death of HIV-infected patients. The mortality rate of CM among the HIV/AIDS population is still as high as 30%. Treatments for CM generally include anti-fungal, anti-viral (HIV) treatment and lowering intracranial pressure.

People who are susceptible to cryptococcosis include:

• HIV positive

• Solid organ transplant recipients

• Idiopathic CD4 lymphopenia

• Monocytopenia

• Autoimmune disease with granulocyte-macrophage colony stimulating factor autoantibody

• Use some small molecule kinase inhibitors that target immune signaling pathways

Diagnosis of CM in HIV-positive patients

Indian ink staining and culture are reliable diagnostic tools for CM, but the positive rate is largely affected by sample sampling, and the long waiting time for culture results is not conducive to rapid diagnosis. Therefore, the diagnosis of CM often requires other auxiliary information, such as the symptoms and signs of the central nervous system and the results of cryptococcal antigen (CrAg) testing.

Compared with non-HIV infected persons, CM with HIV infection has a shorter incubation period and a higher fungal burden. In addition, HIV-related CM is more common with brain parenchymal lesions, and the probability of disseminated infection is higher, but neurological complications such as coma, seizures, and hydrocephalus are less. HIV-infected persons have less obvious symptoms of CM due to impaired immune response, which may lead to delay in diagnosis and treatment and increase the risk of neurological sequelae.

In order to shorten the diagnosis time, the latest WHO guidelines list HIV-positive adults with a CD4 cell count <200 cells/μL as the screening population, and antifungal treatment is initiated in advance based on the cryptococcal antigen titer.

For the accuracy and ease of operation of CrAg detection, WHO recommended in 2011 to use lateral flow immunochromatography (LFIA) to detect cryptococcal polysaccharide antigens and screen patients’ cerebrospinal fluid, serum or plasma. In patients with CM-related symptoms, blood samples tested with LFA may be positive earlier than CSF samples.

Antifungal treatment

So far, the most commonly used antifungal treatment options include: induction period (2 weeks), consolidation period (8 weeks) and maintenance period (secondary prevention, at least 1 year), but the duration of each phase is not fixed , But based on the results of CSF fungal culture and smear and the patient’s clinical condition. When HIV replication decreases during antiretroviral therapy and the CD4 count lasts for at least 3 months> 100/μL, the maintenance treatment can be terminated. Table 1 lists the antifungal treatment options for adult CM recommended by mainstream international guidelines.

Table 1 The first choice of antifungal therapy for adults recommended by mainstream international guidelines                                                                                                           

5-FC, flucytosine; AmB-D, amphotericin B deoxycholate; FLU, fluconazole; L-AmB, amphotericin B liposome

The induction period aims to reduce the fungal load as quickly as possible. As shown in Table 1, it is generally recommended to use a potent bactericide amphotericin B (AmB) for induction. The recent WHO guidelines updated induction therapy, namely shorter AmB exposure, higher daily dose of AmB, and newly added high-dose fluconazole (FLU).

Considering the nephrotoxicity of AmB, IDSA and EACS recommend L-AmB instead of AmB-D, but the former is expensive. The guidelines developed by the Chinese Medical Association (CMA) adopted different methods to minimize the toxicity of AmB: using a lower daily dose and a longer course of treatment of AmB-D, such a long period of time even eliminates the difference between the induction and consolidation periods Limits, see Table 1.

Adjuvant therapy

Adjuvant therapy is mainly divided into two categories: one is immunomodulatory therapy, and the other is adjuvant antifungal therapy, which corresponds to two aspects in the pathological process of CM infection.

Table 2 Classification and summary of adjuvant treatments for CM                                                  

Antiviral therapy

Direct antiviral therapy (ART) is the basic treatment for people living with HIV. For patients with CM, timely administration of ART and effective antifungal therapy accelerate fungal clearance and reduce the risk of recurrence. Attention should be paid to the interaction of antiviral and antifungal drugs. For example, the nephrotoxicity of AmB and tenofovir should be closely monitored, and the combination of voriconazole and high-dose ritonavir (protease inhibitor) should be prohibited.

The ART regimen for patients with CM infection is roughly the same as that for other HIV-positive patients. The controversy mainly focuses on the timing of initiation of ART-naïve patients. The main guidelines suggest delaying the initiation of ART, but the optimal duration is unclear:

The WHO guidelines recommend starting ART 4-6 weeks after antifungal treatment. The Infectious Disease Society of America (IDSA) guidelines suggest that there are differences in the timing of activation, but the basic idea is to reduce the fungal load before ART is activated, thereby reducing the risk of IRIS. 

Treatment of elevated intracranial pressure

Increased intracranial pressure (ICP) is associated with decreased survival. ICP can manifest as disturbance of consciousness, blurred vision, nipple edema, spasm of lower limbs, meningeal irritation, etc. However, some patients have no obvious symptoms, which is related to the decrease of inflammatory response in AIDS patients. Therefore, the WHO guidelines state that once AIDS patients suspect CM, they should receive repeated lumbar punctures to monitor pressure fluctuations, and CSF drainage should be performed when the ICP is elevated.

Lumbar puncture is the main option for reducing intracranial pressure. According to IDSA guidelines, patients with signs or symptoms of increased intracranial pressure can receive repeated lumbar punctures until the pressure returns to normal; for patients who cannot tolerate repeated lumbar punctures or with persistent cerebral edema, CSF shunt can be selected (through Lumbar drainage tube or ventricular incision) or Ommaya reservoir implantation.

Due to lack of sufficient supporting evidence, the use of mannitol and acetazolamide to reduce intracranial pressure is not recommended. The obstruction of frontal arachnoid villi confirmed by pathological examination in CM patients may be the reason for the decreased absorption of CSF. Therefore, the extraction of CSF not only directly reduces the pressure at this time, but in the long run, it can directly reduce the ICP by improving the automatic adjustment function, and the drug cannot achieve this effect.

Summary

CM treatment for HIV-positive patients mainly includes antifungal, antiviral treatment and symptomatic treatment. Although ART can restore the CD4 count, the imbalance between the components of the immune system is still a major obstacle to the cure of CM. On the one hand, it can expand and strengthen the CrAg screening of HIV patients to prevent CM in the early stage. On the other hand, we still need cost-effective antibacterial drugs and induction therapy strategies. Although this article is partly based on international guidelines, individualized treatment should be used as much as possible to reduce the economic burden of patients and avoid adverse events.