Infectious Disease Updates
March 1, 2025
By Carol A. Kemper, MD, FIDSA
Post-COVID Cryptococcosis — Even in Those Without Immunosuppression
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(2):371-377.
As the COVID-19 epidemic evolved, it became clear that post-COVID super-infection, including fungal infection, occurred in a subset of patients. Initially, however, it was a surprise when cases of cryptococcosis occurred post-COVID, especially in non-immunosuppressed persons. These authors conducted a survey of cryptococcal cases occurring within 90 days of a documented SARS-CoV-2 infection. Patients had a positive blood or respiratory culture (confirmed case) or positive serum cryptococcal antigen (CrAg) (probable case); central nervous system (CNS) infection required either a positive cerebrospinal fluid (CSF) culture or CSF CrAg.
A total of 69 adult cases were collected from 29 sites, 96% of them from the United States. The median age was 61 years (range 53-70 years), and two-thirds were male. Of these, 41% had a history of diabetes. More than half (52%) of the cases had no history of immunocompromise or chronic immunosuppressive treatment (other than treatments for COVID). Of the remaining cases, 22% were solid organ transplant recipients, 12% were receiving active chemotherapy for malignancy, 10% had other immunosuppressive conditions, 5% had human immunodeficiency virus (HIV), and 3% other.
Cryptococcosis was diagnosed a median of 22 days post-COVID (range 9-42 days). Twenty-five cases (36%) were diagnosed more than one month following their COVID diagnosis. CSF evaluation was performed in 47% of patients. Disseminated disease in 32%, CNS cryptococcosis in 19%, probable disseminated disease in 26%, and respiratory diseases in 23%.
Diagnostic delay, with ongoing symptoms attributed to cryptococcal infection > 14 days, occurred in 19 (28%) cases. All of these cases were currently hospitalized for COVID; most were receiving treatment with glucocorticoids (one received an interleukin-6 [IL-6] inhibitor). Eleven cases (16%) were diagnosed post-mortem with positive blood (n = 7) or respiratory cultures (n = 4). Nine of these cases were considered immunocompetent. Mortality occurred in 72% of immunocompetent patients vs. 48% of those with immunocompromise. Mortality was much higher than expected for patients with only respiratory disease (> 56%).
At least half of the cases of cryptococcosis associated with SARS-CoV-2 infection occur in persons without chronic immunosuppression. Failure to consider this possibility may contribute to delays in diagnosis, leading to a greater risk of mortality, especially in patients with persistent COVID symptoms, respiratory failure, and acute respiratory distress syndrome (ARDS), which can obscure the diagnosis of concurrent fungal infection.
Think Tularemia
Source: Plymouth M, Lundqvist R, Nystedt A, et al. Targeting tularemia: Clinical, laboratory, and treatment outcomes from an 11-year retrospective observational cohort in Northern Sweden. Clin Infect Dis 2024;78(5):1222-1231.
Cases of tularemia appear to be increasing in frequency in the Northern Hemisphere, perhaps because of increased awareness and improved case detection, as well as reporting of probable cases. In the United States, a total of 2,462 cases of tularemia were reported from 47 states from 2011-2022, reflecting a 56% increase in case numbers relative to the previous 10 years. In the United States, the case definition includes a clinically compatible illness with either a positive culture or a four-fold change in antibody titer between acute and convalescent serum samples. A probable case is defined by a single elevated antibody titer, or detection of Francisella tularensis in a clinical specimen by fluorescent assay, or a positive polymerase chain reaction (PCR). In the United States, the peak incidence occurs in children ages 5-9 years and adult males ≥ 65 years. American Indians and Alaskan natives have five times the incidence of whites. Fifty percent of the cases are reported from four central states (Arkansas, Kansas, Missouri, and Oklahoma).
These authors provided a richly detailed description of tularemia cases occurring in Sweden during a similar time period (2011-2021), where tularemia also appears to be increasing in frequency, with outbreaks of infection occurring at irregular intervals (2012, 2015, and 2019). During this period, a total of 830 tularemia cases were reported to the Swedish Department of Communicable Disease Control. A targeted questionnaire was mailed to cases ≥ 10 years of age at the time of diagnosis, yielding 353 eligible respondents. The mean age at the time of diagnosis was 54 years, with an equal gender distribution.
Of these, 327 were laboratory-confirmed cases, most based on at least one positive serology (96%). Positive cultures for Francisella tularensis sub spp holarctica (“type B”) were obtained in only 18 cases (including 13 peripheral swabs, three blood, one pleural fluid, and one lymph node biopsy). Positive PCR was obtained in 43/43 peripheral skin sites and 1/1 transbronchial aspirate.
Two-thirds of respondents had presented with visible skin ulceration and regional lymphadenopathy (ulceroglandular tularemia); 10.4% had isolated tender or enlarged lymph nodes (glandular tularemia); and 8.8% had chronic suppurative adenopathy, often resulting in surgical resection. Nearly two-thirds (63%) of lymphadenopathy occurred on the lower extremities. Only one case of oculoglandular tularemia was diagnosed. Secondary skin findings, separate from the original site, occurred in 13.5%, and rash was reported in 10.4%.
Forty participants (12.2%) had been diagnosed with pulmonary tularemia; most of these had confirmed pulmonary infiltrates on imaging, while 5/40 cases had atypical findings. Computed tomography (CT) imaging in 15 participants showed that 14 had nodular infiltrates, five had multi-lobar involvement, four had pulmonary abscess, and eight had enlarged mediastinal lymph nodes and four necrotic lymph nodes. “Typhoidal tularemia” with persistent fever without localizing symptoms or physical findings occurred in 24 participants (7.3%).
From the onset of symptoms, there was a median four-day delay in presentation for care. Antibiotics were administered in virtually all of the cases (98.2%) within a median five days from onset of symptoms, although appropriate antibiotics were administered within a median of seven days from diagnosis (four to 14 days). Twenty-two percent of participants never received what is considered first-line therapy (i.e., fluoroquinolone, tetracycline, or aminoglycoside). Retreatment occurred most often in those receiving inappropriate therapy. Among those receiving doxycycline, 34% required retreatment, mostly because of inadequate therapy (duration of treatment ≤ 14 days or inadequate dosing).
Tularemia presents with a broad range of symptoms and findings, largely dependent on the type of exposure or site of inoculation. Contemplating the diagnosis is key to initiation of appropriate therapy, even before laboratory confirmation of infection. Most persons diagnosed with tularemia are not immunocompromised, and the incidence of infection, at least in the United States, is greatest in children and older men. Children especially seem to present with skin manifestations. While we usually think of handling infected animals or arthropod bites (ticks and deer flies) as the most common cause of infection in the United States, mosquito bites were believed to be the likeliest explanation for most cases of ulceroglandular infection in this Swedish cohort.
Carol A. Kemper, MD, FIDSA, is Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation.
Post-COVID Cryptococcosis — Even in Those Without Immunosuppression; Think Tularemia
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