Cryptococcosis After COVID-19: An Emerging Threat

By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A survey initiated by the Mycoses Study Group identified 69 cases of cryptococcosis following COVID-19 infection. The mortality rate was 59%, with cases in both immunocompromised and immunocompetent individuals.

SOURCE: Walker J, McCarty T, McGwin G, et al. Description of cryptococcosis following SARS-CoV-2 infection: A disease survey through the Mycosis Study Group Education and Research Consortium (MSG-19). Clin Infect Dis 2024;78:371-377.

An association has emerged between COVID-19 and invasive fungal infections, particularly Aspergillus and Candida species. The underlying pathophysiology is believed to be a hyper-inflammatory response that causes cytokine release, leading to a down-regulation of CD4 and CD8+ T cells. Recently, case reports have described Cryptococcus infections following COVID-19. Walker and colleagues aimed to further elucidate these observations so that the association between COVID-19 infection and cryptococcosis could be understood better.

The study included patients ≥ 18 years of age with cryptococcal infection within 90 days of infection with SARS-CoV-2 diagnosed between March 1, 2020, and March 31, 2022. Cryptococcal infection was defined as having a positive cryptococcal antigen from serum or cerebrospinal fluid, or a culture with Cryptococcus spp. from any site. Immunodeficiency was classified as having human immunodeficiency virus (HIV), a solid organ transplant, active malignancy receiving treatment, or taking chronic immunosuppressive medications. The investigators created a survey that asked for demographic information and details about the infection. They distributed the survey to providers through the Mycoses Study Group Education and Research Consortium (MSGERC), the Centers for Disease Control and Prevention (CDC) Emerging Infectious Diseases Network, and the infectious diseases community on Twitter (now known as X).

The analysis included 69 patients. The median age was 61 years, and most (68%) were male. Only 25 patients (48%) were immunocompromised. Cryptococcosis was diagnosed a median of 22 days after COVID-19 diagnosis (range, 9-42 days). In 11 cases, the diagnosis was postmortem. The most common symptoms of cryptococcosis overlapped with those of COVID-19 and included cough (n = 30), fever (n = 26), confusion (n = 20), lethargy (n = 18), headache (n = 17), and dyspnea (n = 17). Amphotericin B was used for induction therapy in 39/69 (57%) patients. The reasons for not using amphotericin B were diagnosis made postmortem (n = 11), disease not severe (n = 10), unknown (n = 4), drug not available (n = 3), and toxicity concerns (n = 2).

Outcome data were available for 67/69 (97%) patients. Within six months, 41 (61%) of the patients had died. Mortality was 72% (26/36) in those who were immunocompetent and 48% (15/31) in the immunocompromised (likelihood ratio, 4; P = 0.046). Those with disseminated cryptococcosis had an all-cause mortality of 95% (19/20), while those with pulmonary cryptococcosis had a mortality of 56% (9/16). Among the 13 patients with central nervous system (CNS) cryptococcosis, three had a cerebrovascular accident, two required a shunt due to persistently elevated opening pressure, and one had an immune reconstitution-like syndrome.

The investigators also reported two patients with recurrent cryptococcosis, including one who had a heart transplant nine years previously, then developed CNS cryptococcosis two years afterward. Following a mild COVID-19 infection, this patient again developed CNS cryptococcosis with positive blood and CNS cultures. The patient responded to treatment with amphotericin B and flucytosine, followed by lifelong suppression with fluconazole. The second patient had uncontrolled HIV and a CNS cryptococcal infection two years prior to COVID-19 infection. This patient was not receiving antiretroviral or antifungal therapy, had COVID-19 infection, then developed CNS cryptococcosis again. It was not reported how this patient was managed.

Finally, a patient on immunosuppression for rheumatoid arthritis had positive blood cultures for C. neoformans but a negative serum cryptococcal antigen. The authors explained this as either a prozone phenomenon (which usually is associated with a false-negative response in syphilis testing) or an acapsular strain.

COMMENTARY

This study highlights the emerging association between COVID-19 and Cryptococcus infection. Conventional wisdom is that most cases of cryptococcal infection occur in immunocompromised patients. Notably, a majority (52%) of the patients in the study were immunocompetent, and the mortality rate was higher for the immunocompetent patients than the immunocompromised ones. Follow-up studies should be performed to confirm these findings. In the meantime, patients who develop cryptococcosis after COVID-19 need to be managed prudently, such as by having a low threshold to initiate amphotericin B. Indeed, it can be challenging to differentiate COVID-19 symptoms from cryptococcosis, so a high clinical suspicion is paramount. It is likely that delays in the diagnosis of cryptococcosis contributed to the high (59%) mortality rate observed in the study.

The study had a few limitations. First, only three cases were reported from sites outside the United States, so the results might not be generalizable to other geographic areas. Second, the investigators did not confirm the diagnoses through laboratory data. Finally, the retrospective design may have led to bias by causing the recruitment of memorable cases, thus affecting the reported mortality rate.

Cryptococcosis is a serious infection that causes high morbidity and mortality. Clinicians need to be alert for cryptococcosis in both immunocompetent and immunocompromised patients following COVID-19 infections, even after mild cases.