Response to “Cryptococcal immune reconstitution inflammatory syndrome: Cutaneous clues to disseminated cryptococcosis in a human immunodeficiency virus patient coinfected with tuberculosis on antiretroviral therapy”

Dear Editor,

I read with interest the case report by Vellaisamy et al. titled “Cryptococcal immune reconstitution inflammatory syndrome: Cutaneous clues to disseminated cryptococcosis in a human immunodeficiency virus patient coinfected with tuberculosis on antiretroviral therapy,” published in the Indian Journal of Sexually Transmitted Diseases and AIDS (2025;46:219-22).[1] The authors provide a valuable description of cutaneous manifestations as an early clue to disseminated cryptococcosis in an immunocompromised patient, highlighting the diagnostic importance of skin lesions resembling molluscum contagiosum in the context of HIV and concurrent tuberculosis. However, several aspects of the manuscript warrant clarification or update to align with current evidence, particularly regarding the incidence of cryptococcal immune reconstitution inflammatory syndrome (C-IRIS), diagnostic criteria, and treatment recommendations.

First, the reported incidence of C-IRIS shows inconsistency. The introduction cites an approximate incidence of 4.8% following diagnosis of cryptococcal infection, while the discussion references a range of 39% to 34% (likely a typographical reversal of 34%–39%). Literature indicates substantial variability depending on the cohort and context. Most prospective cohorts report an incidence ranging from approximately 10% to 30% for HIV-associated cryptococcal meningitis–IRIS, depending on the timing of ART initiation and disease burden.[2] The 4.8% figure may pertain to a narrower subgroup or specific definition, but clarifying the source and context would avoid confusion, as overall estimates in advanced HIV are higher when ART is started soon after cryptococcal diagnosis.

Second, the diagnosis of C-IRIS in this case requires careful consideration. The patient, HIV-positive since 2020 with poor compliance to highly active antiretroviral therapy (HAART), presented with a profoundly low CD4 count (35 cells/mm³) and high viral load (215,018 copies/mL), suggesting ongoing severe immunosuppression rather than clear evidence of immune recovery. C-IRIS typically occurs in temporal association with ART initiation or reoptimization, accompanied by signs of immune reconstitution (e.g., rising CD4 count or falling viral load) and inflammatory worsening despite effective antimicrobial therapy. Proposed consensus case definitions distinguish paradoxical IRIS (worsening of treated cryptococcal disease post-ART) from unmasking IRIS (newly apparent cryptococcosis after ART start, often with exaggerated inflammation).[3] Key criteria include timing (symptoms within weeks to months of ART), exclusion of alternative causes (e.g., drug resistance and new infection), and inflammatory features. In this report, details on recent ART adherence improvement, serial immunological trends, or pre-ART cryptococcal antigen status are limited. The presentation may more closely represent progressive disseminated cryptococcosis in untreated/poorly treated HIV, rather than classic IRIS. In the absence of documented immunological improvement following ART initiation or reinitiation, labeling the presentation as C-IRIS remains debatable. Including additional data on these parameters would better substantiate the C-IRIS label.

Third, while the management with intravenous amphotericin B (0.7 mg/kg/day) and therapeutic lumbar puncture aligns with older guidelines,[4] more recent recommendations favor optimized regimens to improve outcomes and reduce toxicity. The World Health Organization (WHO) 2022 guidelines strongly recommend a single high-dose liposomal amphotericin B (10 mg/kg on day 1) combined with flucytosine (100 mg/kg/day for 14 days) and fluconazole (1200 mg/day) as the preferred induction therapy for HIV-associated cryptococcal meningitis, demonstrating superior survival and fewer adverse events compared to conventional amphotericin B regimens.[5] The 2024 global guideline from the European Confederation of Medical Mycology (ECMM), International Society for Human and Animal Mycology (ISHAM), and American Society for Microbiology (ASM) endorses similar combination approaches, emphasizes routine cryptococcal antigen screening in advanced HIV (CD4 <200 cells/mm³), and supports adjunctive corticosteroids (e.g., prednisone 0.5–1.0 mg/kg/day for 2–6 weeks) only for severe central nervous system complications in confirmed IRIS.[6] Incorporating flucytosine and considering liposomal formulations where available, these regimens could enhance efficacy, even in resource-constrained settings such as India.

This case effectively illustrates the persistent challenge of cryptococcosis in HIV, especially with coinfections and delayed ART adherence, and reinforces the value of cutaneous signs for prompt diagnosis. Greater emphasis on standardized diagnostic criteria for cryptococcal immune reconstitution inflammatory syndrome, clear documentation of immunological response to antiretroviral therapy, and alignment with contemporary evidence-based treatment guidelines would further enhance the clinical clarity and educational impact of such reports. Careful distinction between progressive opportunistic infection and true IRIS is essential, as it carries important implications for therapeutic decision-making and patient outcomes in advanced HIV disease.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.