Cryptococcal meningitis (CM) is the most common adult fungal meningitis in large parts of the world with high morbidity and mortality (1–3). An exaggerated immunological response after starting antiretroviral therapy (ART) treatment was initially observed in HIV-infected patients with CM and termed as immune reconstitution inflammatory syndrome (IRIS) (4). In the HIV-negative CM patients, neurological deterioration is not due to antifungal treatment failure but due to the enhancement of immune response, which is called post-infectious inflammatory response syndrome (PIIRS) (5, 6). Here, we report an 82-year-old male patient with CM who developed PIIRS after initial antifungal therapy. To the best of our knowledge, CM-PIIRS had not been reported at such an old age.

To the best of our knowledge, this is the oldest patient reported for CM-PIIRS. He developed PIIRS in 4 months after initial antifungal therapy. Then, he was treated with corticosteroids for 2 months and recovered clinically. However, the clinical manifestation, CSF, and brain MRI results got worse again on the next day after corticosteroid withdrawal. He received corticosteroids again and subsequently obtained a complete resolution of symptoms.

PIIRS is defined as a deterioration in neurological status in a previously healthy patient with CM after CSF fungal culture converting to negative following optimal therapy (7, 8). Unlike IRIS where immune reconstitution occurs after the initiation of ART, PIIRS may be a response to released fungal antigens during therapy and reductions in immunomodulatory components including capsular fragments (9). Although the exact reason for CM-PIIRS remains unclear, some studies have also been carried out. Our previous study indicated that baseline hearing impairment and high CSF pressure (>230 mmH2O) may be predictors of PIIRS in HIV-negative immunocompetent CM patients (10, 11), and a prospective study including 25 patients showed that 88% of non-HIV CM patients developed PIIRS after VPS (10, 11). As some literature reported (5, 6, 11–20), our case got initial neurological improvement after the use of corticosteroids. However, this case developed PIIRS again on the next day after 2 months of corticosteroid treatment withdrawal, and we have to think about the question: what dose of corticosteroids should we use and how long should we use corticosteroids in CM-PIIRS?

US guidelines suggested that 0.5–1.0 mg/kg per day of prednisone equivalent and 2–6 weeks of corticosteroid treatment were a reasonable method for patients with severe CM-IRIS (21), while in CM-PIIRS, there were no clinical guidelines to instruct clinicians how to use corticosteroids. As shown in Table 1, there are currently two common methods of using corticosteroids for treating CM-PIIRS: (1) pulse methylprednisolone (1 g IV daily for 5–7 days) taper therapy (6) and (2) a lower dose of corticosteroid (dexamethasone 10–20 mg/day IV or prednisolone 1 mg/kg/day PO) taper therapy. In a recent prospective study (6), CM-PIIRS patients received pulse methylprednisolone 1 g IV daily for 7 days followed by 1 mg/kg/day prednisone for 1 month and then tapered by 5 mg every month based on their clinical response and brain MRI findings. Romani et al. (13) described a CM-PIIRS patient with X-linked Hyper IgM syndrome who received 6 days of high-dose methylprednisolone (1 g) which was slowly tapered over 6 months. However, we treat CM-PIIRS patients with low-dose corticosteroid taper therapy in our department. As shown in our previous published study (14), CM-PIIRS patients were treated with intravenous dexamethasone (10–20 mg daily), then oral prednisone (30–40 mg/day), and tapered off by time. There are other reports on the use of low-dose corticosteroid taper therapy in CM-PIIRS (14–16, 18). For instance, Kulkarni et al. (18) reported a CM-PIIRS patient who received oral prednisolone (1 mg/kg/day) for 1 week and then tapered over 2 months, and this patient had significant clinical improvement and was discharged in a stable condition. The above two methods of using corticosteroids seem to be effective for CM-PIIRS, but further research is needed to evaluate which method is better.

Our case showed the CM-PIIRS patient who got worse in clinical manifestation and brain imaging again just one day after corticosteroid withdrawal. The phenomenon seen in our case was also similar to previous studies (16, 20). One report (16) showed an immunocompetent 34-year-old CM patient who developed PIIRS. Dexamethasone 12 mg/day was initiated and tapered gradually and eventually stopped in 1 month. However, the patient experienced headache 4 days after corticosteroid withdrawal. Therefore, prednisolone (20 mg/day) was given for another 2 weeks and slowly tapered over the next 3 months with sustained clinical improvement. Moreover, another report (20) showed that CM-PIIRS occurred in a 46-year-old female when the steroids were discontinued; she received corticosteroids for more than 10 months in total. Therefore, how long should we use corticosteroids in CM-PIIRS? Our previous report (14) showed that the corticosteroid therapy median duration was 4 months and Mehta et al. (19) reported corticosteroid salvage therapy (CST), followed by maintenance therapy using oral prednisone (20 mg daily); the median duration was 8 months. In addition, Cheng et al. (15) reported a CM-PIIRS patient who received corticosteroids for more than 1 year and Kathiresu et al. (17) reported a CM-PIIRS patient who received corticosteroids for more than 6 months. Moreover, there were other reports that showed a more than 2-month (10, 6, 5 months, respectively) course of corticosteroids in CM-PIIRS patients (6, 13, 16). According to the above literature summary and our own clinical experience, we consider that a 2-month course may not be enough to treat CM-PIIRS, especially severe cases. Moreover, the course of corticosteroids in CM-PIIRS should be based on clinical, CSF, and brain MRI results.

Due to the decline of immune function, the elderly individuals are often more susceptible to infectious diseases including central nervous system (CNS) infections (22–24). In a study including 99 CM patients, 38.4% (38/99) were elderly CM patients (age >65 years old) which had a high mortality rate (36.8%, 14/38) (25). Therefore, we should pay attention to the treatment of elderly CM patients. In our case, he developed PIIRS and got significant improvement in clinical manifestation and brain MRI after receiving corticosteroids. However, as far as we know, we should use corticosteroids with caution for elderly patients because corticosteroids have some adverse events such as osteopenia and fracture (26, 27). Fortunately, no severe steroid-induced adverse events occurred in this case. In general, the use of corticosteroids in elderly CM-PIIRS patients is probably not only effective but also safe if we closely monitor patients’ conditions.

PIIRS is an important cause of poor outcome in CM patients. Therefore, it is very important to recognize and actively treat in these patients. Even in elderly patients, corticosteroid treatment is still beneficial. Moreover, 2 months of corticosteroid treatment may be not enough to treat CM-PIIRS.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The study involving human participants was reviewed and approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. Informed consent was obtained from the individual participant included in the study.

YJ and FP were involved in the literature review, planning, and writing of the manuscript. JyL, JL, B-eQ, SY, AW, LY, ZS, and XX collected the data. YJ and FP were involved in the case identification, literature review, and planning and editing of the manuscript. YJ, FP, JyL, and JL were involved in the planning, writing, and editing of the manuscript. All authors contributed to the article and approved the submitted version.

This work is supported by grants from the Natural Science Foundation of China (82071265) and Guangzhou Science and Technology Planning Project (202102010288).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.