INTRODUCTION
Cryptococcus neoformans infection is an opportunistic fungal infection that occurs mainly in immunocompromised patients, such as those with acquired immune deficiency syndrome, undergoing organ transplant, or who are treated with immunosuppressants or chemotherapy.1,2 In the pandemic caused by SARS-CoV-2, there have been reports of fungal infections associated with COVID-19. To date, the reported cases have mainly been invasive pulmonary aspergillosis, mucormycosis, Pneumocystis jiroveci, and candidiasis.3–5 Cryptococcal infections associated with COVID-19 have rarely been reported in immunocompetent patients.6,7 Here, we report a case of cryptococcal meningitis in an immunocompetent patient previously treated with immunosuppressive therapy for COVID-19 in South Korea.
CASE DESCRIPTION
A 78-year-old female presented to the emergency department with dyspnea and drowsiness. The underlying diseases were hypertension, hyperlipidemia, and well-controlled diabetes, and she was diagnosed with COVID-19 4 days earlier. The patient was not vaccinated against COVID-19. On physical examination, the mental status was drowsy with severe hypoxia that required supplemental oxygen. Chest radiography showed peripheral and lower zone opacities, and computed tomography (CT) revealed multiple ground-glass infiltrates suggestive of COVID-19 pneumonia (Figure 1). Brain CT showed hypoattenuation of the left middle cerebral artery region, suggesting acute infarction (Figure 2). She was started on mechanical ventilation. Aspirin and clopidogrel were administered to treat brain infarction. Intravenous (IV) piperacillin/tazobactam was administered because combined bacterial pneumonia could not be ruled out. The treatment of COVID-19 pneumonia was initiated with IV remdesivir. Baricitinib (by mouth) 4 mg was administered for 2 weeks as initial treatment combined with IV dexamethasone. Dexamethasone 6 mg was initially administered, followed by 12 mg for 10 days, but her chest radiography findings and O2 requirements did not improve; therefore, IV methylprednisolone 1 mg/kg was subsequently administered and tapered for 2 months. The patient underwent a tracheostomy and went to the general ward on day 60 with a mildly drowsy mental state.
Chest radiograph. (A) Bilateral peripheral and lower lung zone opacities of atypical pneumonia. Chest computed tomography. (B) Multiple ground-glass opacities in the periphery and lower lobes, consistent with atypical pneumonia with diffuse alveolar damage.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 2; 10.4269/ajtmh.23-0457
Brain computed tomography shows hypoattenuation in the left middle cerebral artery division, suggesting acute infarction.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 2; 10.4269/ajtmh.23-0457
On day 86, the patient’s mental status changed from drowsiness to stupor. Brain magnetic resonance imaging revealed changes suggestive of multifocal acute infarctions and meningitis (Figure 3). She underwent spinal tapping, and cerebrospinal fluid analysis revealed a white blood cell count of 140 cells/µL, protein level of 453.7 mg/dL, glucose level of 64 mg/dL, and adenosine deaminase of 24.8 IU/L. The cerebrospinal fluid (CSF) cryptococcal Ag titer was 1:256, and C. neoformans was grown in the CSF culture. Induction treatment with liposomal amphotericin B and flucytosine was initiated. After 10 days of treatment, the culture of C. neoformans in the CSF was negative. Induction treatment was performed for 3 weeks, followed by consolidation with fluconazole. Despite aggressive management, her state of consciousness did not improve, and she died of septic shock on day 123.
Brain diffusion magnetic resonance imaging. Axial diffusion-weighted image (DWI). (A) Hyperintensities in multiple lesions indicative of multifocal acute infarctions. High signal intensity along the right pons and in both cerebellum on axial DWI (B and C), along with slightly low signal intensity on the axial apparent diffusion coefficient map (D), suggest the possibility of meningitis.
Citation: The American Journal of Tropical Medicine and Hygiene 110, 2; 10.4269/ajtmh.23-0457
DISCUSSION
This case is meaningful in that a rare case of cryptococcal meningitis occurred after COVID-19 infection in a patient who previously immunocompetent. Treatment of COVID-19 with corticosteroids and immunomodulatory agents may be a predisposing factor for C. neoformans infections. COVID-19 remains an important disease worldwide, and countermeasures are required against opportunistic fungal infections that may accompany this disease.
Cryptococcosis is a fungal infection caused by Cryptococcus species, primarily C. neoformans. Cryptococcus species are ubiquitous in the environment and usually cause invasive infections in immunocompromised individuals. Recently, cryptococcal infections have been reported in patients with COVID-19. Table 1 lists the cases of cryptococcal infection in patients with COVID-19. Cryptococcosis after the diagnosis of COVID-19 occurred more frequently in patients with underlying comorbidities or immunodeficiency, of whom 32% were HIV-infected and 28% were transplant recipients. However, some reports have shown cryptococcosis in patients who did not have predisposing factors at baseline.6–8
Cases of cryptococcal infection in patients with COVID-19
| Case | Age | Sex | Underlying Disease | Treatment of COVID-19 | Site of infection/diagnosis | Pathogen | Treatment of cryptococcal infection | Outcome |
|---|---|---|---|---|---|---|---|---|
| Choi et al.6 | 46 | M | None | None | Pulmonary/BAL culture | C. neoformans | Fluconazole | Alive |
| Ghanem et al.7 | 73 | F | None | Corticosteroid | Meningeal/CSF culture | C. neoformans | Amphotericin B + flucytosine | Alive |
| Thota et al.8 | 76 | F | HTN, osteoarthritis | Corticosteroid Tocilizumab Convalescent plasma | Disseminated/blood culture, CSF culture | C. neoformans | Amphotericin B + | Alive |
| Gil et al.12 | 59 | M | HTN, DM, obesity | Corticosteroid | Disseminated/blood culture | C. neoformans | Liposomal amphotericin B, fluconazole | Alive |
| Sharma et al.13 | 60 | M | HTN, DM, hypothyroidism | Corticosteroid | Pulmonary/lung biopsy | C. neoformans | Liposomal amphotericin B, fluconazole | Alive |
| Alegre-Gonzalez et al.14 | 78 | M | HTN, DM, CKD | Corticosteroid | Disseminated/blood culture, CSF culture | C. neoformans | Amphotericin B + flucytosine, fluconazole | Dead |
| Karnik et al.15 | 57 | M | HTN | Corticosteroid | Disseminated/blood culture, CSF culture | C. neoformans | Liposomal amphotericin B + flucytosine | Dead |
| Khatib et al.16 | 60 | M | HTN, DM, CAD | Corticosteroid Tocilizumab | Disseminated/blood culture | C. neoformans | Amphotericin B + flucytosine | Dead |
| Thyagarajan et al.17 | 75 | M | HTN, DM, obesity | Corticosteroid Convalescent plasma | Disseminated/blood culture | C. neoformans | None | Dead |
| Traver et al.18 | 59 | M | COPD, CHF, DM | Corticosteroid Cyclophosphamide | Pulmonary/BAL culture | C. neoformans | Liposomal amphotericin B + flucytosine | Dead |
COVID-19, coronavirus disease 2019; BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; HTN, hypertension; DM, diabetes mellitus; CKD, chronic kidney disease; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; M, male; F, female.
The association between COVID-19 and cryptococcosis remains unclear. SARS-CoV-2 infection causes immune dysregulation and may affect the T cell response.9,10 Lymphocytes are an important component of the host’s defense mechanism against cryptococcal infection, and alterations in the immune system after COVID-19 may affect cryptococcal infection.10,11 It is also possible that immune suppression therapy with corticosteroids, tocilizumab, and baricitinib may suppress the immune system, resulting in opportunistic infections. Chastain et al.8,11 reported that cryptococcosis with COVID-19 were more likely to have received tocilizumab or baricitinib than those without cryptococcosis. Two reports showed cases of cryptococcosis in patients treated with dexamethasone for COVID-19 without other immune-modulating therapies, and the use of corticosteroids may have contributed to cryptococcosis.7,12
To the best of our knowledge, this is the first case report of cryptococcal meningitis in a patient with COVID-19 in Korea. More cases can be expected during the COVID-19 pandemic, given the widespread use of corticosteroids and immunomodulatory agents to treat COVID-19. We suggest that cryptococcal infection can also occur in immunocompetent hosts with COVID-19 and should be considered an opportunistic infection in patients with COVID-19, especially when treated with immune suppression therapy.
ACKNOWLEDGMENTS
We sincerely thank all the medical staff, paramedics, and other staff members of Seoul Medical Center for their work in caring for patients with COVID-19. The American Society of Tropical Medicine and Hygiene has waived the Open Access fee for this COVID-19 article and assisted with publication expenses.
REFERENCES
- 1.↑
Hajjeh RA et al., 1999. Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. Cryptococcal Active Surveillance Group. J Infect Dis 179: 449–454.
- 2.↑
May RC , Stone NR , Wiesner DL , Bicanic T , Nielsen K , 2016. Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol 14: 106–117.
- 3.↑
Bartoletti M et al., 2021. Epidemiology of invasive pulmonary aspergillosis among intubated patients with COVID-19: a prospective study. Clin Infect Dis 73: e3606–e3614.
- 4.↑
Hoenigl M et al., 2022. The emergence of COVID-19 associated mucormycosis: a review of cases from 18 countries. Lancet Microbe 3: e543–e552.
- 5.↑
Salehi M , Ahmadikia K , Badali H , Khodavaisy S , 2020. Opportunistic fungal infections in the epidemic area of COVID-19: a clinical and diagnostic perspective from Iran. Mycopathologia 185: 607–611.
- 6.↑
Choi HS , 2022. Pulmonary cryptococcosis after recovery from COVID-19 in an immunocompetent patient: a rare case report. Medicine (Baltimore) 101: e30143.
- 7.↑
Ghanem H , Sivasubramanian G , 2021. Cryptococcus neoformans meningoencephalitis in an immunocompetent patient after COVID-19 infection. Case Rep Infect Dis 2021: 5597473.
- 8.↑
Thota DR , Ray B , Hasan M , Sharma K , 2022. Cryptococcal meningoencephalitis during convalescence from severe COVID-19 pneumonia. Neurohospitalist 12: 96–99.
- 9.↑
Merad M , Martin JC , 2020. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 20: 355–362.
- 10.↑
Levitz SM , Dupont MP , 1993. Phenotypic and functional characterization of human lymphocytes activated by interleukin-2 to directly inhibit growth of Cryptococcus neoformans in vitro. J Clin Invest 91: 1490–1498.
- 11.↑
Chastain DB , Kung VM , Golpayegany S , Jackson Brittany T , Franco-Paredes C , Vargas Barahona L , Thompson GR III , Henao-MartÃnez AF , 2022. Cryptococcosis among hospitalised patients with COVID-19: a multicentre research network study. Mycoses 65: 815–823.
- 12.↑
Gil Y , Gil YD , Markou T , 2021. The emergence of cryptococcemia in COVID-19 infection: a case report. Cureus 13: e19761.
- 13.↑
Sharma S , Agrawal G , Das S , 2022. COVID-19-associated pulmonary Cryptococcosis: a rare case presentation. Indian J Crit Care Med 26: 129–132.
- 14.↑
Alegre-González D , Herrera S , Bernal J , Soriano A , Bodro M , 2021. Disseminated Cryptococcus neoformans infection associated to COVID-19. Med Mycol Case Rep 34: 35–37.
- 15.↑
Karnik K , Wu Y , Ruddy S , Quijano-Rondan B , Urban C , Turett G , Yung L , Prasad N , Yoon J , Segal-Maurer S , 2022. Fatal case of disseminated cryptococcal infection and meningoencephalitis in the setting of prolonged glucocorticoid use in a Covid-19 positive patient. IDCases 27: e01380.
- 16.↑
Khatib MY , Ahmed AA , Shaat SB , Mohamed AS , Nashwan AJ , 2021. Cryptococcemia in a patient with COVID-19: a case report. Clin Case Rep 9: 853–855.
- 17.↑
Thyagarajan RV , Mondy KE , Rose DT , 2021. Cryptococcus neoformans blood stream infection in severe COVID-19 pneumonia. IDCases 26: e01274.
- 18.↑
Traver EC , Malavé Sánchez M , 2022. Pulmonary aspergillosis and cryptococcosis as a complication of COVID-19. Med Mycol Case Rep 35: 22–25.