Development of cryptococcal immune reconstitution inflammatory syndrome 41 months after the initiation of antiretroviral therapy in an AIDS patient

Cryptococcal meningitis is one of the most lethal fungal infections in patients with acquired immune deficiency syndrome (AIDS) [1]. As an opportunistic infection, it may develop in patients whose CD4 cell counts are less than 100 cells/μL. Before the introduction of combination antiretroviral therapy (cART), cryptococcal meningitis developed in 6–10 % of AIDS patients [1]. However, since the introduction of cART, the incidence of and mortality from cryptococcal meningitis and other opportunistic infections have decreased markedly in AIDS patients [2].

Some patients experience immune reconstitution inflammatory syndrome (IRIS) after the initiation of cART. IRIS is thought to occur when cART causes immune system recovery and thereby elicits paradoxical inflammatory responses to either previously diagnosed and treated or subclinical infections [3].

IRIS has been described in association with multiple opportunistic pathogens, such as Mycobacterium avium complex, Mycobacterium tuberculosis, Cryptococcus neoformans, cytomegalovirus, and hepatitis viruses. Although IRIS was initially described in human immunodeficiency virus (HIV)-infected patients who had started cART, it is now known to occur in other settings as well, such as in organ transplantation, patients after cessation of tumor necrosis factor (TNF)-α inhibitors, and pregnancy [4‐6]. Cryptococcal IRIS most frequently presents as recurrent meningitis; however, it may manifest as intracranial space-occupying lesions and non-central nervous system presentations (e.g., lymphadenitis, pneumonitis, and ophthalmologic complications) [7]. Previous studies have reported that cryptococcal IRIS develops in 8–45 % of HIV-infected patients with cryptococcosis who responded to cART, despite the use of antifungal therapy. The mortality rate among these patients ranges from 8 to 30 % [7‐10].

Generally, IRIS occurs within a median of 12 weeks after starting cART [11]. Similarly, most cases of cryptococcal IRIS have been shown to develop within 12 months after the initiation of cART, with median intervals ranging from 1 to 10 months [7]. However, IRIS can also occur outside of the usual range. For example, cryptococcal IRIS has been reported as early as 4 days and as late as 37 months after starting cART [7, 8, 12].

In the following section, we present the case of an AIDS patient who developed symptoms of cryptococcal IRIS 41 months after starting cART. To the best of our knowledge, the time between cART initiation and the onset of cryptococcal IRIS in this patient is the longest that has been reported in the literature.

In December 2009, a 59-year-old man developed Pneumocystis jirovecii pneumonia (PCP) and was diagnosed as having HIV-1 infection. His CD4 T cell count was 44 cells/μL and his HIV RNA load was 16,000 copies/mL at diagnosis. He also had chronic hepatitis B. Two weeks after completing the treatment for PCP using adjunctive corticosteroids, he was admitted to our hospital again after presenting with a gradually worsening headache and fever. On admission, he had no neck stiffness, photophobia, or focal neurological abnormality. A computed tomography (CT) scan of the head did not show any pathological findings. A lumbar puncture revealed an opening pressure of 350 mm H₂O, cell counts of 7/µL (100 % lymphocytes), protein levels of 29 mg/dL, and glucose levels of 40 mg/dL. Yeasts were seen on a cerebrospinal fluid (CSF) smear. Both the CSF and blood cultures subsequently became positive for C. neoformans with minimum inhibitory concentrations of 1.0 µg/mL for amphotericin B, 4.0 µg/mL for fluconazole (FLCZ), and 4.0 µg/mL for flucytosine (5-FC). The patient’s initial blood and CSF cryptococcal antigen titers were 1:16,384 and 1:4096, respectively. A chest X-ray film showed no abnormalities; however, white perivascular infiltrates that were compatible with fungal retinitis/endophthalmitis were observed in both ocular fundi. The patient was therefore diagnosed with disseminated cryptococcosis with meningitis, retinitis, and cryptococcemia. He was treated with amphotericin B lipid complex (L-AmB) 200 mg/day and 5-FC 6000 mg/day (which was decreased to 4000 mg/day because of the adverse effect of pancytopenia) for 2 weeks, followed by L-AmB 200 mg/day and FLCZ 400 mg/day for another 2 weeks. The initial treatment was followed by maintenance therapy (FLCZ 200 mg/day). Fungal clearance was observed in the CSF obtained 15 days after starting antifungal therapy. Initial and subsequent CSF findings are shown in Table 1.

In March 2010, 5 weeks after the initiation of antifungal therapy for cryptococcosis, cART with tenofovir/emtricitabine plus lopinavir/ritonavir (LPV/r) was started. In May 2010, raltegravir replaced LPV/r due to the hepatotoxicity associated with LPV/r. The HIV RNA load in the blood became undetectable within 3 months after starting cART. His CD4 T-cell count recovered gradually to about 200 cells/μL without recurrence of PCP or cryptococcosis. To provide maintenance therapy for cryptococcal meningitis, FLCZ was continued alongside cART.

In mid-August 2013, after 41 months of cART, the patient had a mild headache accompanied by mild nausea. Approximately 1 week later, he presented with a generalized tonic–clonic seizure featuring worsening paralysis of the right leg. He was still receiving cART and FLCZ maintenance therapy for cryptococcosis, with good adherence. His CD4 T-cell count was 193 cells/μL, and his HIV RNA load was undetectable upon admission. A CT scan of the head revealed low-density areas in the subcortical region and deep white matter with surrounding edema in the left frontal and right temporal lobes. A brain magnetic resonance imaging (MRI) scan (Fig. 1a) showed high signal intensity on T2-weighted images without obvious mass effect. Contrast-enhanced MRI showed enhancement along the brain surface and cerebral sulcus, but the parenchyma showed little enhancement. A lumbar puncture was performed and showed clear CSF (9 white blood cells/μL) as well as normal glucose and protein levels (Table 1). India ink stains and cultures of the CSF sample were negative. Blood and CSF cryptococcal antigen tests were both positive; however, titers had decreased to 1:64 and 1:4, respectively, in comparison with the titers that had been obtained in 2010 (Table 1). Because we did not perform blood or CSF cryptococcal antigen tests between March 2010 and August 2013, it could not be determined whether the blood and CSF cryptococcal antigen titers had ever fallen below 1:64 and 1:4, respectively. Polymerase chain reaction tests of the CSF for herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and JC virus were all negative. A diagnostic brain biopsy of the left frontal lobe was therefore performed. The pathological examination revealed inflammatory cells and many rounded fungi that were detected on periodic acid-Schiff and Grocott stains in the subarachnoid cavity and periarteriolar spaces (Fig. 2). These findings were compatible with cryptococcal meningoencephalitis with white matter edema. Cultures of the brain tissue specimen were negative for Cryptococcus species and other fungal and bacterial pathogens. Thus, the patient was diagnosed with cryptococcal meningoencephalitis (mainly involving the meninges) associated with IRIS.

He was treated again with L-AmB 200 mg/day and 5-FC 3000 mg/day in addition to corticosteroid adjunctive therapy [prednisolone 50 mg (1 mg/kg) daily] for 2 weeks. This was followed by maintenance therapy with FLCZ 300 mg/day (which was adjusted according to renal function). The prednisolone dose was gradually tapered over 6 months. Discontinuation of antiretroviral therapy was not necessary during the course of the disease. His headache and right leg weakness resolved quickly, and the follow-up brain MRI scan obtained 3 weeks after the start of therapy showed an overall improvement with a marked decrease in the size of the white matter lesions (Fig. 1b).