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Missed opportunities to identify cryptococcosis in COVID-19 patients: a case report and literature review

Missed opportunities to identify cryptococcosis in COVID-19 patients: a case report and... 1066363 TAI0010.1177/20499361211066363Therapeutic Advances in Infectious Disease X(X)DB Chastain, AF Henao-Martínez research-article20212021 Infectious Diseases Due to Therapeutic Special Collection Immunosuppression Therapeutic Advances in Infectious Disease Case Report Ther Adv Infectious Dis Missed opportunities to identify 2022, Vol. 9: 1–10 h DOI: 10.1177/ ttps://doi.org/10.1177 /20499361211066363 https://doi.org/10.1177/20499361211066363 cryptococcosis in COVID-19 patients: © The Author(s), 2022. Article reuse guidelines: a case report and literature review sagepub.com/journals- permissions Daniel B. Chastain , Andrés F. Henao-Martínez , Austin C. Dykes, Gregory M. Steele, Laura Leigh Stoudenmire, Geren M. Thomas, Vanessa Kung and Carlos Franco-Paredes Abstract: SARS-CoV-2 may activate both innate and adaptive immune responses ultimately leading to a dysregulated immune response prompting the use of immunomodulatory therapy. Although viral pneumonia increases the risk of invasive fungal infections, it remains unclear whether SARS-CoV-2 infection, immunomodulatory therapy, or a combination of both are responsible for the increased recognition of opportunistic infections in COVID-19 patients. Cases of cryptococcosis have previously been reported following treatment with corticosteroids, interleukin (IL)-6 inhibitors, and Janus kinase (JAK) inhibitors, for patients with autoimmune diseases, but their effect on the immunologic response in patients with Correspondence to: COVID-19 remains unknown. Herein, we present the case of a patient with COVID-19 who Daniel B. Chastain Department of Clinical & received high-dose corticosteroids and was later found to have cryptococcosis despite no Administrative Pharmacy, traditional risk factors. As our case and previous cases of cryptococcosis in patients with College of Pharmacy, University of Georgia, 1000 COVID-19 demonstrate, clinicians must be suspicious of cryptococcosis in COVID-19 patients Jefferson Street, Albany, GA 31701, USA. who clinically deteriorate following treatment with immunomodulatory therapies. daniel.chastain@uga.edu Andrés F. Henao-Martínez Vanessa Kung Keywords: COVID-19, Cryptococcus, cytokine release syndrome, immunotherapy, SARS-CoV-2 Division of Infectious Diseases, University of Colorado, Anschutz Received: 6 October 2021; revised manuscript accepted: 24 November 2021. Medical Campus, Aurora, CO, USA Austin C. Dykes Introduction decreasing among persons living with HIV (PLH) Department of Clinical & SARS-CoV-2 can activate both innate and adap- due to increased uptake of antiretroviral therapy Administrative Pharmacy, 5 College of Pharmacy, tive immune responses in patients ultimately lead- (ART). However, an increasing number of cases University of Georgia, ing to a dysregulated immune response. Due to of cryptococcosis have been identified among new Albany, GA, USA the widespread use of immunomodulatory therapy, populations of patients with cell-mediated immu- Gregory M. Steele Infectious Diseases, including high-dose corticosteroids, interleukin nodeficiencies, including solid organ transplant Phoebe Putney Memorial (IL)-1 and IL-6 inhibitors, as well as Janus kinase (SOT) recipients and non-HIV-infected, non- Hospital, Albany, GA, USA Laura Leigh Stoudenmire (JAK) inhibitors, as part of the medical manage- transplant patients with malignancies, autoim- Department of Pharmacy, 2,3 ment of COVID-19, an increasing number of mune diseases, diabetes mellitus, cirrhosis, as well Phoebe Putney Memorial Hospital, Albany, GA, USA patients may experience an impaired immune as those receiving immunosuppressive medica- 4 6–10 Geren M. Thomas response. Consequently, compromising host tions. Herein, we present the case of a patient Department of Pharmacy, immunity in COVID-19 patients could provide the with COVID-19 who received immunomodula- John D. Archbold Memorial Hospital, perfect opportunity for secondary infections with or tory therapy with high-dose corticosteroids and Thomasville, GA, USA reactivation of previously latent diseases, such as was later found to have cryptococcosis. Carlos Franco-Paredes latent tuberculosis infections, strongyloidiasis, Division of Infectious Diseases, University aspergillosis, mucormycosis, or cryptococcosis. of Colorado, Anschutz Patient case Medical Campus, Aurora, CO, USA Specifically, Cryptococcus neoformans is frequently A man in his early 70s, who was a nursing home Hospital Infantil de México, associated with advanced HIV disease manifesting resident, was sent to an outside hospital (OSH) in Federico Gómez, México as meningoencephalitis, but rates have been the Southeastern United States in late November City, México journals.sagepub.com/home/tai 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Infectious Disease 9 Figure 1. Timeline of hospitalization. Figure depicts daily (D) timeline of hospitalization at the outside hospital (OSH) and subsequent transfer to our facility. Baseline laboratory data are presented upon admission to both facilities and include the following: Alk phos, alkaline phosphatase (range: 30–120 units/L); ALT, alanine transferase (10–40 units/L); Anti-HBc, hepatitis B virus core antibody (range: nonreactive); AST, aspartate transferase (10–40 units/L); BUN, blood urea nitrogen (range: 8–20 mg/dL); Cl, chloride (range: 98–106 mEq/L); Glu, glucose (range: 77–99 mg/dL); HBsAg, hepatitis B virus surface antigen (range: nonreactive); HCO, bicarbonate (range: 23–28 mEq/L); Hct, hematocrit (range: 42–50%); HCV Ab, hepatitis C virus antibody (range: nonreactive); Hgb, hemoglobin (range: 14–18 g/dL); K, potassium (range: 3.5–5 mEq/L); Lymphocytes (range: 30–45%); Na, sodium (range: 135–145 mEq/L); Neutrophils (range: 50–70%); PLT, platelet (range: 150–450 K/μL); SCr, serum creatinine (range: 0.70–1.30 mg/dL); WBC, white blood cell (range: 3.5–10 K/mm ). 2020, due to hypoxia following a recent diagnosis appearance consistent with COVID-19. Baseline of SARS-CoV-2 infection. His past medical his- chemistry and hematology laboratory values tory included a cerebrovascular accident resulting revealed leukopenia and lymphopenia but were in left hemiplegia and hemiparesis, idiopathic otherwise unremarkable and reflected his underly- peripheral autonomic neuropathy, spinal stenosis ing CKD (Figure 1). He was provided supple- with bilateral lower extremity radiculopathy, atrial mental oxygen via nasal cannula and treated with fibrillation, hypertension, coronary artery disease, ceftriaxone and azithromycin for 7 days. Although dyslipidemia, chronic obstructive pulmonary dis- he was deemed not to be a candidate for remdesi- ease, gastroesophageal reflux disease, stage 3 vir at that time due to CKD, he received dexa- chronic kidney disease (CKD), benign prostatic methasone for 10 days in combination with hypertrophy, obesity, major depressive disorder, convalescent plasma. Blood cultures and sputum and vascular dementia for which he took amlodi- cultures were collected on admission but remained pine, aspirin, atorvastatin, dabigatran, donepezil, sterile. famotidine, memantine, metoprolol tartrate, ome- prazole, pregabalin, tamsulosin, and valproic acid. Over the next 10 days, he remained afebrile, but On admission, he complained of fevers, shortness his respiratory function continued to deteriorate of breath, nonproductive cough, loose stools, and on nasal cannula, and he was transitioned to non- anorexia, but denied headache, visual disturbance, rebreather (NRB) mask. The previously identi- hemoptysis, arthralgia, myalgia, nausea, vomiting, fied multifocal infiltrates persisted on follow-up or rashes. His O saturation was 91% on room air chest radiography (CXR). Due to decreased O 2 2 and computed tomography (CT) of the chest saturation to 70% and bluish-gray appearance, revealed multifocal infiltrates with a ground-glass the patient required intubation, mechanical 2 journals.sagepub.com/home/tai DB Chastain, AF Henao-Martínez et al. ventilation, and initiation of vasopressors, which part of the therapeutic armamentarium for prompted a transfer to our institution. COVID-19. The most frequently identified OIs include invasive pulmonary aspergillosis and Upon arrival, he was admitted to the intensive mucormycosis. Clinical presentation varies care unit (ICU), where he remained sedated, depending on organ involvement and overlap with mechanically ventilated, and on vasopressors. He COVID-19, but often develops 1 to 2 weeks after 13,14 was subsequently started on remdesivir for 5 hospitalization. Advanced age, chronic pul- days, in addition to IV methylprednisolone 60 mg monary disease, and treatment with antimicrobial IV every 8 h for 2 days followed by a gradual taper therapy were identified as risk factors for corona- throughout his hospitalization. His initial blood virus disease-associated pulmonary aspergillosis 13,15 and urine cultures were sterile, but multiple tra- (CAPA), whereas diabetes mellitus was the cheal aspirate cultures revealed methicillin-resist- most common risk factor among patients with ant Staphylococcus aureus. Despite an unchanged COVID-19-associated mucormycosis (CAM). CXR and successful extubation, he was started In addition, many of these patients received on IV vancomycin on day 3, but was transitioned immunomodulatory therapies for COVID-19, to linezolid after experiencing an acute kidney specifically corticosteroids and IL-6 inhibitors, injury for a combined total of 16 days. which likely contributes to the increasing inci- 13–15 dence of CAPA and CAM. As our case dem- The patient continued to improve and was trans- onstrates, cryptococcosis is yet another important ferred out of the ICU on a high-flow nasal can- opportunistic pathogen that should be considered nula over the next 4 days, but became febrile and by clinicians caring for patients with COVID-19 experienced hypoxia, lethargy, as well as hypoten- who received immunomodulatory agents. sion requiring intubation and mechanical ventila- tion with a subsequent transfer back to ICU. While cryptococcosis primarily affects immunode- Blood cultures revealed yeast on Gram stain, and ficient patients, an increasing number of cases have he was started on micafungin. Unfortunately, the been reported in immunocompetent patients, in patient’s blood pressure and respiratory function which some of these patients do not have identifi- continued to deteriorate over the next 24 h, and able risk factors. In most situations, immunocom- he expired. Post-mortem, the previously detected petent hosts can eradicate C. neoformans after yeasts grew on Sabouraud Dextrose Agar inhalation, but C. neoformans may survive by evad- (Emmons modification) which were identified via ing the host immune response and forming a cryp- Thermo Scientific™ RapID™ Yeast Plus System tococcal granuloma or residing in phagocytic 16,17 (RapID; Thermo Fisher Scientific, Lenexa, cells, thereby establishing a latent infection. Kansas) as C. neoformans. Molecular identifica- Following the development of disease state- (e.g. 6–8,10,18 tion and antifungal susceptibility testing were not diabetes mellitus, cirrhosis, sarcoidosis, etc.) performed due to limited capabilities in the local or medication- (e.g. corticosteroids, chemother- 19,20 microbiology laboratory. Serum cryptococcal apy, etc.) induced immune defects in these antigen (CrAg) lateral flow assay (LFA) was also previously immunocompetent patients, the latent not performed due to low suspicion of cryptococ- C. neoformans infection can reactivate resulting in cosis in this patient and limited data describing detectable cryptococcosis. cryptococcosis in patients with COVID-19 at the time of this patient’s care. Indeed, eight previous cases of cryptococcosis in patients with COVID-19 have been reported 22–29 (Table 1) based on a PubMed literature search Discussion on 14 September 2021, using ‘Cryptococcus’ and There is increasing recognition of opportunistic ‘COVID-19’. Of those reports, the median age infections (OIs) in COVID-19 patients with was 74 (range: 24–78) years and 80% were men. underlying medical conditions such as uncon- Seventy-five percent had chronic comorbidi- 11,12 22,25–29 22,25–27,29 trolled diabetes mellitus. Although the precise ties, of which hypertension (83%) 25,27 mechanism remains unknown, the most likely and diabetes mellitus (33%) were most com- pathophysiology is multifactorial involving mon. In addition, two patients were receiving cytokine dysregulation and impaired cell-medi- immunosuppressive medications: prednisone for ated immunity due to SARS-CoV-2 combined autoimmune hemolytic anemia and tacrolimus in with receipt of immunomodulatory therapies as combination with prednisone due to renal journals.sagepub.com/home/tai 3 Therapeutic Advances in Infectious Disease 9 4 journals.sagepub.com/home/tai Table 1. Reports of cryptococcosis in patients with COVID-19. Case Age (years) Sex Medical, surgical, or social history Clinical course Outcome Heller et al. 24 M Born in Central America, but • Complained of headaches, shortness of breath, No neurologic immigrated to the United States pleuritic pain, myalgias, nausea, vomiting for deficits at 3 months prior to admission, approximately 3 weeks prior to hospitalization 2.5-month follow- otherwise unremarkable • SARS-CoV-2 RNA detected 1 week prior to up hospitalization • On admission, underwent lumbar puncture due to signs of meningeal inflammation upon admission which revealed increased opening pressure (55 cm H O), colorless CSF with 108 WBC/μL (81% lymphocytes), 47 mg/dL protein, and 42 mg/dL glucose • C. neoformans isolated from CSF cultures and treated with amphotericin B and flucytosine • Subsequently diagnosed with HIV (VL 138,000 copies/mL, CD4 16 cells/μL) and started on B/F/ TAF Passarelli et al. 75 M Hypertension, deceased donor Died on day 18 • Presented with cough and progressive dyspnea × kidney transplant 3 years ago 4 days with SARS-CoV-2 detected upon admission (tacrolimus 4 mg/day and • Chest CT revealed bilateral ground-glass opacities prednisone 5 mg/day), cirrhosis for which ceftriaxone and clindamycin were started while prednisone was increased to 30 mg/day and tacrolimus was discontinued • After 4 days, required mechanical ventilation and started on IV hydrocortisone 50 mg every 6 h • Developed septic shock on day 12 despite treatment with meropenem, vancomycin, and fluconazole • C. neoformans isolated from blood cultures on day 12 and 16 Woldie et al. 24 M Autoimmune hemolytic anemia • Presented with fevers, myalgias, cough with SARS- Died prior to (prednisone 20 mg/day) CoV-2 detected upon admission identification of • His prednisone dose was increased to 1.5 mg/kg/ cryptococcosis day and cyclophosphamide 50 mg every 12 h was started • Discharged after 13 days, but readmitted 1 week later due to persistent headache which then progressed to decreased consciousness and new onset seizures • MRI brain revealed necrotizing encephalitis for which IV methylprednisolone 1 g/day and IVIG 1 g/kg were initiated • Sustained a cardiac arrest prior to undergoing LP • C. neoformans was isolated from blood cultures obtained on the second hospitalization (Continued) DB Chastain, AF Henao-Martínez et al. journals.sagepub.com/home/tai 5 Table 1. (Continued) Case Age (years) Sex Medical, surgical, or social history Clinical course Outcome Cafardi et al. 78 M Hypertension, COPD • Presented with fever, myalgia, hypoxia, dyspnea, Died approximately headache, and diarrhea with SARS-CoV-2 detected 20 days after upon admission identification of • Remdesivir × 5 days, IV methylprednisolone 40 mg cryptococcosis every 12 h, and inhaled recombinant sialidase × 10 days were initiated • After 16 days, clinically improved but then deteriorated with onset of fevers and respiratory failure requiring mechanical ventilation and bronchoscopy • C. neoformans was isolated from respiratory cultures, whereas serum CrAg was not detected • Received LAMB × 6 days but sustained AKI and was transitioned to isavuconazole Ghanem and 73 F R THA 2 weeks prior to admission, • Febrile and hypoxic with patchy bilateral infiltrates Discharged to Sivasubramanian otherwise unremarkable on CXR postoperatively a rehabilitation • SARS-CoV-2 detected and received azithromycin × 5 facility days and dexamethasone × 10 days • After 7 days of therapy, developed new onset gait instability, falls, and aphasia with CT head demonstrating hydrocephalus • Underwent EVD placement and CSF analysis revealed 25 WBC/μL, 173 mg/dL protein, and <10 mg/dL glucose • C. neoformans isolated from CSF cultures and treated with amphotericin and flucytosine Khatib et al. 60 M Hypertension, diabetes mellitus, • Required ICU admission and MV due to COVID-19, Died 10 days after ischemic heart disease received three doses of tocilizumab, multiple doses identification of of methylprednisolone, and hydrocortisone cryptococcosis • Required HD for AKI • Developed candidemia (Candida parapsilosis) and received anidulafungin • C. neoformans isolated from blood cultures while receiving anidulafungin so switched to amphotericin and flucytosine (Continued) Therapeutic Advances in Infectious Disease 9 6 journals.sagepub.com/home/tai Table 1. (Continued) Case Age (years) Sex Medical, surgical, or social history Clinical course Outcome Thota et al. 76 F Hypertension, osteoarthritis, • Presented with diarrhea, confusion, and weakness Discharged to gastroesophageal reflux disease with SARS-CoV-2 detected upon admission LTCF but remained • Cefepime, ampicillin, vancomycin, and IV comatose methylprednisolone 40 mg every 12 h were initiated due to fevers and lactic acidosis • On day 3, required mechanical ventilation and then received convalescent plasma, remdesivir, tocilizumab, and inhaled budesonide • Clinically improved and discharged to a SNF, but readmitted with fever and encephalopathy after 14 days • MRI brain demonstrated numerous acute and subacute infarcts in the cerebral and cerebellar hemispheres without enhancement • CSF analysis revealed 87 WBC/μL, 3530 RBC/μL, 193 mg/dL protein, and <5 mg/dL glucose, and CrAg titer > 1:2560 • C. neoformans was isolated from CSF and blood cultures and treated with amphotericin and flucytosine × 3 weeks • Transitioned to fluconazole after CSF sterilized Thyagarajan et al. 75 M Diabetes mellitus, hypertension, • Presented with fever and difficulty breathing with Died prior to obesity, osteoarthritis SARS-CoV-2 detected upon admission requiring identification of ICU admission and MV cryptococcosis • Remdesivir × 5 days, IV dexamethasone 6 mg daily × 10 days, and convalescent plasma • Developed VAP due to MRSA on day 17 and was treated with vancomycin then linezolid • Continued to clinically deteriorate and was transitioned to comfort measures • C. neoformans isolated from blood cultures on day 26 A phase III randomized placebo-controlled study to examine the efficacy and safety of DAS181 for the treatment of lower respiratory tract parainfluenza infection in immunocompromised subjects (https://clinicaltrials.gov/ct2/show/NCT03808922). AKI, acute kidney injury; B/F/TAF, bictegravir/emtricitabine/tenofovir alafenamide; CrAg, cryptococcal antigen; CSF, cerebrospinal fluid; CT, computed tomography; CXR, chest radiography; EVD, external ventricular drain; F, female; HD, hemodialysis; ICU, intensive care unit; IV, intravenous; LAMB, liposomal amphotericin B; LP, lumbar puncture; LTCF, long term care facility; M, male; MRSA, methicillin resistant Staphylococcus aureus; MV, mechanical ventilation; R, right; RBC, red blood cell; SNF, skilled nursing facility; THA, total hip arthroplasty; VAP, ventilator acquired pneumonia; VL, viral load; WBC, white blood cell. DB Chastain, AF Henao-Martínez et al. transplantation. Characterization of symptoms necessary for reactivation, which in this case caused by cryptococcosis was challenging due to include SARS-CoV-2 infection–induced lympho- overlap with COVID-19. However, due to low penia combined with prolonged high-dose corti- suspicion for cryptococcosis many patients clini- costeroid treatment. Mechanisms to predict and cally deteriorated, some of which died prior to prevent reactivation of latent cryptococcosis are detection of cryptococcosis. needed given the increasing incidence of immu- nosuppressive diseases and widespread use of During hospitalization, 25% of patients received immunosuppressive medications. tocilizumab, and 88% received corticosteroids. In the only case where corticosteroids were not Asymptomatic treatment-naïve PLH with CD4 administered for COVID-19, diagnosis of crypto- cell counts ⩽100 to 200 cells/µL undergo screen- coccosis subsequently led to a new diagnosis of ing for cryptococcosis using serum cryptococcal 24 32,33 HIV, whereas C. neoformans was most commonly antigen (CrAg) testing. Among those with identified after receiving immunomodulatory ther- detectable CrAg, CSF should be evaluated to apy in all other cases; C. neoformans was isolated determine whether the cryptococci have dissemi- from blood cultures in 63% (n = 5) of patients. Of nated to the central nervous system (CNS). Early the 38% (n = 3) of patients who underwent cere- identification and treatment of cryptococcus in brospinal fluid (CSF) evaluation, C. neoformans PLH with low CD4 cell counts has led to was detected in all CSF cultures. Overall mortality decreased mortality attributable to cryptococcal 34–36 was 63%, of which two patients died before identi- meningoencephalitis. Unfortunately, similar 27,28 fication of cryptococcosis. recommendations to detect cryptococcal antigen- emia and ultimately identify localized pulmonary 22,23,29 In four cases, including our patient, no tra- cryptococcosis or disseminated cryptococcosis do ditional risk factors for cryptococcosis were iden- not exist in HIV-uninfected immunodeficient tified. Notably, our patient had a glycated patients nor immunocompetent patients. hemoglobin (A1C) of 5.6% (A1C ⩾ 6.5% diag- Diagnosis of cryptococcosis in non-HIV non- nostic for diabetes), but did not undergo HIV transplant patients is often missed or significantly testing. While viral pneumonia increases the risk delayed compared to PLH or organ transplant 37,38 of invasive fungal infections, it remains unclear recipients resulting in lower survival rates, as whether SARS-CoV-2 infection, immunomodu- the sensitivity of CrAg LFA to detect CrAg in latory therapy, or a combination of both were serum, while still relatively high, is lower than responsible for increased susceptibility to acute that in PLH. Unfortunately, the sensitivity of infection with or reactivation of C. neoformans in serum CrAg is unknown in COVID-19 patients these patients with COVID-19. Although much with an impaired immune response. As such, the of the pathogenesis of cryptococcosis in COVID- risk of dissemination is increased compared to 19 patients is poorly defined due to limited details immunocompetent patients, therefore necessitat- in other case reports, we suspect our patient had ing an evaluation for meningoencephalitis in latent cryptococcosis which reactivated because COVID-19 patients with serologic or microbio- of SARS-CoV-2 infection–induced lymphopenia logic evidence of cryptococcosis. and corticosteroid treatment. Blood cultures obtained on admission at the OSH were sterile. An optimal treatment regimen for cryptococcosis Based on a rat model of pulmonary cryptococco- has not been identified in non-HIV nontransplant 40,41 sis which mirrors human infection, C. neoformans patients due to limited data. As a result, most persists as a granuloma within the lung despite treatment regimens are based on efficacy data from 17,21 initial containment and no clinical symptoms. PLH and SOT recipients, but depend on the extent Following receipt of corticosteroid therapy, of disease. A combination of lipid-associated formu- increased fungal burden and extrapulmonary dis- lations of amphotericin B (LFAB), such as liposo- semination were observed to a greater extent mal amphotericin B (LAmB) or amphotericin B when corticosteroid therapy was administered lipid complex (ABLC), plus flucytosine is most within 4 weeks of initial infection with C. neofor- effective due to rapid fungicidal activity and is con- mans. However, similar findings were not sidered first line for induction therapy among observed with late stages of latent cryptococcosis patients with meningoencephalitis, disseminated suggesting multiple mechanisms might be (e.g. involvement of two or more noncontiguous journals.sagepub.com/home/tai 7 Therapeutic Advances in Infectious Disease 9 sites), or severe pulmonary disease (e.g. diffuse pul- therapy, most often a combination of LFAB plus monary infiltrates). In cases of meningoencephalitis, flucytosine, thereby halting or eliminating further antifungal therapy should be combined with daily dissemination and improve overall mortality. therapeutic lumbar punctures or placement of a lumbar drain or ventriculostomy to reduce intracra- Author contributions nial pressure (ICP). Indeed, most patients who were Daniel B. Chastain: Conceptualization; Data still alive after identification of cryptococcosis curation; Visualization; Writing – original draft; received an LFAB in combination with flucyto- Writing – review & editing. 23–25,29 sine, though few patients underwent CSF Andrés F. Henao-Martínez: Conceptualization; 23,24,29 examination. Supervision; Writing – review & editing. Austin C. Dykes: Writing – original draft; While LFABs are preferred due to lower risk of Writing – review & editing. nephrotoxicity, amphotericin b deoxycholate Gregory M. Steele: Writing – review & editing. (AmBd) can be used if LAmB or ABLC are una- Laura Leigh G. Stoudenmire: Writing – review vailable. Many resource-limited countries are & editing. unable to access flucytosine due to limited availa- Geren M. Thomas: Writing – review & editing. 43,44 bility and prohibitive costs, requiring use of Vanessa Kung: Writing – review & editing. less efficacious regimens such as high dose flucon- Carlos Franco-Paredes: Conceptualization; 40,41 azole with or without AmBd. A prolonged Supervision; Writing – review & editing. duration of induction therapy of 4 weeks, or longer in the presence of neurologic complications, is Conflict of interest statement required in non-HIV nontransplant patients. After The authors declared no potential conflicts of clinical improvement with induction therapy, flu- interest with respect to the research, authorship, conazole 800 mg per day should be initiated as and/or publication of this article. consolidation therapy for at least 8 weeks followed by 200 to 400 mg per day as maintenance therapy Funding for at least 1 year. However, the duration of anti- The authors received no financial support for the fungal therapy is somewhat dependent on resolu- research, authorship, and/or publication of this tion of the underlying immunodeficiency allowing article. for gradual restoration of immune function. Ethics approval Our report did not require ethical board approval Conclusion as it described the treatment of a single patient Cases of cryptococcosis have previously been which does not meet the federal definition of reported following short- or long-term initiation of human subjects research. This case was docu- corticosteroids, IL-6 inhibitors, and JAK inhibitors mented in the context of routine care and the for patients with autoimmune diseases, but it information presented was anonymized in accord- remains unknown how the use of one or a combi- ance with the Declaration of Helsinki. nation of these therapies will directly or indirectly alter immunologic response in patients with Patient consent COVID-19. Clinicians must be suspicious of cryp- Consent was unable to be obtained as the patient tococcosis in COVID-19 patients who clinically is deceased and their relatives were not contacta- deteriorate following treatment with immunomod- ble. As such, details have been removed from the ulatory therapies as signs and symptoms of crypto- case description to ensure anonymity. coccosis may overlap with COVID-19. Given the utility of CrAg LFA to detect CrAg in serum cou- ORCID iDs pled with the high rate of missed opportunities to Daniel B. Chastain https://orcid.org/0000- identify cryptococcosis and dire outcomes in non- 0002-4018-0195 HIV nontransplant patients, early recognition, Andrés F. Henao-Martínez https://orcid.org/ perhaps through the use of a CrAg screen-and- 0000-0001-7363-8652 treat strategy, prior to administration of immu- nomodulatory therapies in COVID-19 patients Carlos Franco-Paredes https://orcid.org/ will result in prompt administration of antifungal 0000-0001-8757-643X 8 journals.sagepub.com/home/tai DB Chastain, AF Henao-Martínez et al. 11. Rodriguez-Morales AJ, Sah R, Millan-Oñate J, References et al. COVID-19 associated mucormycosis: the 1. Giamarellos-Bourboulis EJ, Netea MG, Rovina urgent need to reconsider the indiscriminate use N, et al. Complex immune dysregulation in of immunosuppressive drugs. Ther Adv Infect COVID-19 patients with severe respiratory Dis. Epub ahead of print 18 June 2021. DOI: failure. Cell Host Microbe 2020; 27: 992–1000.e3. 10.1177/20499361211027065. 2. NIH. COVID-19 treatment guidelines panel. 12. Salehi M, Ahmadikia K, Badali H, et al. 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Clin Infect fungal infection associated with COVID-19. Open Dis 2018; 66: S152–S159. Forum Infect Dis 2021; 8: ofab016. 34. Ssekitoleko R, Kamya MR and Reingold AL. 23. Ghanem H and Sivasubramanian G. Primary prophylaxis for cryptococcal meningitis Cryptococcus neoformans meningoencephalitis and impact on mortality in HIV: a systematic in an immunocompetent patient after COVID- review and meta-analysis. Future Virol 2013; 8. 19 infection. Case Rep Infect Dis 2021; 2021: DOI: 10.2217/fvl.13.71. 35. Hakim J, Musiime V, Szubert AJ, et al. Enhanced 24. Heller HM, Gonzalez RG, Edlow BL, et al. Case prophylaxis plus antiretroviral therapy for 40-2020: a 24-year-old man with headache and advanced HIV infection in Africa. N Engl J Med Covid-19. N Engl J Med 2020; 383: 2572–2580. 2017; 377: 233–245. 25. Khatib MY, Ahmed AA, Shaat SB, et al. 36. Awotiwon AA, Johnson S, Rutherford GW, et al. Cryptococcemia in a patient with COVID-19: a Primary antifungal prophylaxis for cryptococcal case report. 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Autoimmune hemolytic anemia in a 24-year- Performance of the cryptococcal antigen lateral old patient with COVID-19 complicated by flow assay in non-HIV-related cryptococcosis. secondary cryptococcemia and acute necrotizing J Clin Microbiol 2016; 54: 460–463. encephalitis: a case report and review of 40. Henao-Martínez AF, Chastain DB and Franco- literature. J Med Cases 2020; 11: 362–365. Paredes C. Treatment of cryptococcosis in non- 29. Thota DR, Ray B, Hasan M, et al. Cryptococcal HIV immunocompromised patients. Curr Opin meningoencephalitis during convalescence from Infect Dis 2018; 31: 278–285. severe COVID-19 pneumonia. Neurohospitalist. 41. Perfect JR, Dismukes WE, Dromer F, et al. Epub ahead of print 3 May 2021. DOI: Clinical practice guidelines for the management 10.1177/19418744211009766. of cryptococcal disease: 2010 update by the 30. Passerini M, Terzi R, Piscaglia M, et al. infectious diseases society of America. Clin Infect Disseminated cryptococcosis in a patient with Dis 2010; 50: 291–322. metastatic prostate cancer who died in the 42. Hamill RJ, Sobel JD, El-Sadr W, et al. coronavirus disease 2019 (COVID-19) outbreak. Comparison of 2 doses of liposomal amphotericin Cureus 2020; 12: e8254. B and conventional amphotericin B deoxycholate 31. 2.Classification and diagnosis of diabetes: for treatment of AIDS-associated acute standards of medical care in diabetes-2021. cryptococcal meningitis: a randomized, double- Diabetes Care 2021; 44: S15–S33. blind clinical trial of efficacy and safety. Clin Infect Dis 2010; 51: 225–232. 32. Mfinanga S, Chanda D, Kivuyo SL, et al. Cryptococcal meningitis screening and 43. Merry M and Boulware DR. Cryptococcal community-based early adherence support in meningitis treatment strategies affected by the people with advanced HIV infection starting explosive cost of flucytosine in the United States: antiretroviral therapy in Tanzania and Zambia: a cost-effectiveness analysis. Clin Infect Dis 2016; an open-label, randomised controlled trial. Lancet 62: 1564–1568. 2015; 385: 2173–2182. 44. Kneale M, Bartholomew JS, Davies E, et al. Visit SAGE journals online journals.sagepub.com/ 33. Ford N, Shubber Z, Jarvis JN, et al. CD4 Global access to antifungal therapy and its home/tai cell count threshold for cryptococcal antigen variable cost. J Antimicrob Chemother 2016; 71: SAGE journals screening of HIV-infected individuals: a 3599–3606. 10 journals.sagepub.com/home/tai http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Infectious Disease SAGE

Missed opportunities to identify cryptococcosis in COVID-19 patients: a case report and literature review

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1066363 TAI0010.1177/20499361211066363Therapeutic Advances in Infectious Disease X(X)DB Chastain, AF Henao-Martínez research-article20212021 Infectious Diseases Due to Therapeutic Special Collection Immunosuppression Therapeutic Advances in Infectious Disease Case Report Ther Adv Infectious Dis Missed opportunities to identify 2022, Vol. 9: 1–10 h DOI: 10.1177/ ttps://doi.org/10.1177 /20499361211066363 https://doi.org/10.1177/20499361211066363 cryptococcosis in COVID-19 patients: © The Author(s), 2022. Article reuse guidelines: a case report and literature review sagepub.com/journals- permissions Daniel B. Chastain , Andrés F. Henao-Martínez , Austin C. Dykes, Gregory M. Steele, Laura Leigh Stoudenmire, Geren M. Thomas, Vanessa Kung and Carlos Franco-Paredes Abstract: SARS-CoV-2 may activate both innate and adaptive immune responses ultimately leading to a dysregulated immune response prompting the use of immunomodulatory therapy. Although viral pneumonia increases the risk of invasive fungal infections, it remains unclear whether SARS-CoV-2 infection, immunomodulatory therapy, or a combination of both are responsible for the increased recognition of opportunistic infections in COVID-19 patients. Cases of cryptococcosis have previously been reported following treatment with corticosteroids, interleukin (IL)-6 inhibitors, and Janus kinase (JAK) inhibitors, for patients with autoimmune diseases, but their effect on the immunologic response in patients with Correspondence to: COVID-19 remains unknown. Herein, we present the case of a patient with COVID-19 who Daniel B. Chastain Department of Clinical & received high-dose corticosteroids and was later found to have cryptococcosis despite no Administrative Pharmacy, traditional risk factors. As our case and previous cases of cryptococcosis in patients with College of Pharmacy, University of Georgia, 1000 COVID-19 demonstrate, clinicians must be suspicious of cryptococcosis in COVID-19 patients Jefferson Street, Albany, GA 31701, USA. who clinically deteriorate following treatment with immunomodulatory therapies. daniel.chastain@uga.edu Andrés F. Henao-Martínez Vanessa Kung Keywords: COVID-19, Cryptococcus, cytokine release syndrome, immunotherapy, SARS-CoV-2 Division of Infectious Diseases, University of Colorado, Anschutz Received: 6 October 2021; revised manuscript accepted: 24 November 2021. Medical Campus, Aurora, CO, USA Austin C. Dykes Introduction decreasing among persons living with HIV (PLH) Department of Clinical & SARS-CoV-2 can activate both innate and adap- due to increased uptake of antiretroviral therapy Administrative Pharmacy, 5 College of Pharmacy, tive immune responses in patients ultimately lead- (ART). However, an increasing number of cases University of Georgia, ing to a dysregulated immune response. Due to of cryptococcosis have been identified among new Albany, GA, USA the widespread use of immunomodulatory therapy, populations of patients with cell-mediated immu- Gregory M. Steele Infectious Diseases, including high-dose corticosteroids, interleukin nodeficiencies, including solid organ transplant Phoebe Putney Memorial (IL)-1 and IL-6 inhibitors, as well as Janus kinase (SOT) recipients and non-HIV-infected, non- Hospital, Albany, GA, USA Laura Leigh Stoudenmire (JAK) inhibitors, as part of the medical manage- transplant patients with malignancies, autoim- Department of Pharmacy, 2,3 ment of COVID-19, an increasing number of mune diseases, diabetes mellitus, cirrhosis, as well Phoebe Putney Memorial Hospital, Albany, GA, USA patients may experience an impaired immune as those receiving immunosuppressive medica- 4 6–10 Geren M. Thomas response. Consequently, compromising host tions. Herein, we present the case of a patient Department of Pharmacy, immunity in COVID-19 patients could provide the with COVID-19 who received immunomodula- John D. Archbold Memorial Hospital, perfect opportunity for secondary infections with or tory therapy with high-dose corticosteroids and Thomasville, GA, USA reactivation of previously latent diseases, such as was later found to have cryptococcosis. Carlos Franco-Paredes latent tuberculosis infections, strongyloidiasis, Division of Infectious Diseases, University aspergillosis, mucormycosis, or cryptococcosis. of Colorado, Anschutz Patient case Medical Campus, Aurora, CO, USA Specifically, Cryptococcus neoformans is frequently A man in his early 70s, who was a nursing home Hospital Infantil de México, associated with advanced HIV disease manifesting resident, was sent to an outside hospital (OSH) in Federico Gómez, México as meningoencephalitis, but rates have been the Southeastern United States in late November City, México journals.sagepub.com/home/tai 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Infectious Disease 9 Figure 1. Timeline of hospitalization. Figure depicts daily (D) timeline of hospitalization at the outside hospital (OSH) and subsequent transfer to our facility. Baseline laboratory data are presented upon admission to both facilities and include the following: Alk phos, alkaline phosphatase (range: 30–120 units/L); ALT, alanine transferase (10–40 units/L); Anti-HBc, hepatitis B virus core antibody (range: nonreactive); AST, aspartate transferase (10–40 units/L); BUN, blood urea nitrogen (range: 8–20 mg/dL); Cl, chloride (range: 98–106 mEq/L); Glu, glucose (range: 77–99 mg/dL); HBsAg, hepatitis B virus surface antigen (range: nonreactive); HCO, bicarbonate (range: 23–28 mEq/L); Hct, hematocrit (range: 42–50%); HCV Ab, hepatitis C virus antibody (range: nonreactive); Hgb, hemoglobin (range: 14–18 g/dL); K, potassium (range: 3.5–5 mEq/L); Lymphocytes (range: 30–45%); Na, sodium (range: 135–145 mEq/L); Neutrophils (range: 50–70%); PLT, platelet (range: 150–450 K/μL); SCr, serum creatinine (range: 0.70–1.30 mg/dL); WBC, white blood cell (range: 3.5–10 K/mm ). 2020, due to hypoxia following a recent diagnosis appearance consistent with COVID-19. Baseline of SARS-CoV-2 infection. His past medical his- chemistry and hematology laboratory values tory included a cerebrovascular accident resulting revealed leukopenia and lymphopenia but were in left hemiplegia and hemiparesis, idiopathic otherwise unremarkable and reflected his underly- peripheral autonomic neuropathy, spinal stenosis ing CKD (Figure 1). He was provided supple- with bilateral lower extremity radiculopathy, atrial mental oxygen via nasal cannula and treated with fibrillation, hypertension, coronary artery disease, ceftriaxone and azithromycin for 7 days. Although dyslipidemia, chronic obstructive pulmonary dis- he was deemed not to be a candidate for remdesi- ease, gastroesophageal reflux disease, stage 3 vir at that time due to CKD, he received dexa- chronic kidney disease (CKD), benign prostatic methasone for 10 days in combination with hypertrophy, obesity, major depressive disorder, convalescent plasma. Blood cultures and sputum and vascular dementia for which he took amlodi- cultures were collected on admission but remained pine, aspirin, atorvastatin, dabigatran, donepezil, sterile. famotidine, memantine, metoprolol tartrate, ome- prazole, pregabalin, tamsulosin, and valproic acid. Over the next 10 days, he remained afebrile, but On admission, he complained of fevers, shortness his respiratory function continued to deteriorate of breath, nonproductive cough, loose stools, and on nasal cannula, and he was transitioned to non- anorexia, but denied headache, visual disturbance, rebreather (NRB) mask. The previously identi- hemoptysis, arthralgia, myalgia, nausea, vomiting, fied multifocal infiltrates persisted on follow-up or rashes. His O saturation was 91% on room air chest radiography (CXR). Due to decreased O 2 2 and computed tomography (CT) of the chest saturation to 70% and bluish-gray appearance, revealed multifocal infiltrates with a ground-glass the patient required intubation, mechanical 2 journals.sagepub.com/home/tai DB Chastain, AF Henao-Martínez et al. ventilation, and initiation of vasopressors, which part of the therapeutic armamentarium for prompted a transfer to our institution. COVID-19. The most frequently identified OIs include invasive pulmonary aspergillosis and Upon arrival, he was admitted to the intensive mucormycosis. Clinical presentation varies care unit (ICU), where he remained sedated, depending on organ involvement and overlap with mechanically ventilated, and on vasopressors. He COVID-19, but often develops 1 to 2 weeks after 13,14 was subsequently started on remdesivir for 5 hospitalization. Advanced age, chronic pul- days, in addition to IV methylprednisolone 60 mg monary disease, and treatment with antimicrobial IV every 8 h for 2 days followed by a gradual taper therapy were identified as risk factors for corona- throughout his hospitalization. His initial blood virus disease-associated pulmonary aspergillosis 13,15 and urine cultures were sterile, but multiple tra- (CAPA), whereas diabetes mellitus was the cheal aspirate cultures revealed methicillin-resist- most common risk factor among patients with ant Staphylococcus aureus. Despite an unchanged COVID-19-associated mucormycosis (CAM). CXR and successful extubation, he was started In addition, many of these patients received on IV vancomycin on day 3, but was transitioned immunomodulatory therapies for COVID-19, to linezolid after experiencing an acute kidney specifically corticosteroids and IL-6 inhibitors, injury for a combined total of 16 days. which likely contributes to the increasing inci- 13–15 dence of CAPA and CAM. As our case dem- The patient continued to improve and was trans- onstrates, cryptococcosis is yet another important ferred out of the ICU on a high-flow nasal can- opportunistic pathogen that should be considered nula over the next 4 days, but became febrile and by clinicians caring for patients with COVID-19 experienced hypoxia, lethargy, as well as hypoten- who received immunomodulatory agents. sion requiring intubation and mechanical ventila- tion with a subsequent transfer back to ICU. While cryptococcosis primarily affects immunode- Blood cultures revealed yeast on Gram stain, and ficient patients, an increasing number of cases have he was started on micafungin. Unfortunately, the been reported in immunocompetent patients, in patient’s blood pressure and respiratory function which some of these patients do not have identifi- continued to deteriorate over the next 24 h, and able risk factors. In most situations, immunocom- he expired. Post-mortem, the previously detected petent hosts can eradicate C. neoformans after yeasts grew on Sabouraud Dextrose Agar inhalation, but C. neoformans may survive by evad- (Emmons modification) which were identified via ing the host immune response and forming a cryp- Thermo Scientific™ RapID™ Yeast Plus System tococcal granuloma or residing in phagocytic 16,17 (RapID; Thermo Fisher Scientific, Lenexa, cells, thereby establishing a latent infection. Kansas) as C. neoformans. Molecular identifica- Following the development of disease state- (e.g. 6–8,10,18 tion and antifungal susceptibility testing were not diabetes mellitus, cirrhosis, sarcoidosis, etc.) performed due to limited capabilities in the local or medication- (e.g. corticosteroids, chemother- 19,20 microbiology laboratory. Serum cryptococcal apy, etc.) induced immune defects in these antigen (CrAg) lateral flow assay (LFA) was also previously immunocompetent patients, the latent not performed due to low suspicion of cryptococ- C. neoformans infection can reactivate resulting in cosis in this patient and limited data describing detectable cryptococcosis. cryptococcosis in patients with COVID-19 at the time of this patient’s care. Indeed, eight previous cases of cryptococcosis in patients with COVID-19 have been reported 22–29 (Table 1) based on a PubMed literature search Discussion on 14 September 2021, using ‘Cryptococcus’ and There is increasing recognition of opportunistic ‘COVID-19’. Of those reports, the median age infections (OIs) in COVID-19 patients with was 74 (range: 24–78) years and 80% were men. underlying medical conditions such as uncon- Seventy-five percent had chronic comorbidi- 11,12 22,25–29 22,25–27,29 trolled diabetes mellitus. Although the precise ties, of which hypertension (83%) 25,27 mechanism remains unknown, the most likely and diabetes mellitus (33%) were most com- pathophysiology is multifactorial involving mon. In addition, two patients were receiving cytokine dysregulation and impaired cell-medi- immunosuppressive medications: prednisone for ated immunity due to SARS-CoV-2 combined autoimmune hemolytic anemia and tacrolimus in with receipt of immunomodulatory therapies as combination with prednisone due to renal journals.sagepub.com/home/tai 3 Therapeutic Advances in Infectious Disease 9 4 journals.sagepub.com/home/tai Table 1. Reports of cryptococcosis in patients with COVID-19. Case Age (years) Sex Medical, surgical, or social history Clinical course Outcome Heller et al. 24 M Born in Central America, but • Complained of headaches, shortness of breath, No neurologic immigrated to the United States pleuritic pain, myalgias, nausea, vomiting for deficits at 3 months prior to admission, approximately 3 weeks prior to hospitalization 2.5-month follow- otherwise unremarkable • SARS-CoV-2 RNA detected 1 week prior to up hospitalization • On admission, underwent lumbar puncture due to signs of meningeal inflammation upon admission which revealed increased opening pressure (55 cm H O), colorless CSF with 108 WBC/μL (81% lymphocytes), 47 mg/dL protein, and 42 mg/dL glucose • C. neoformans isolated from CSF cultures and treated with amphotericin B and flucytosine • Subsequently diagnosed with HIV (VL 138,000 copies/mL, CD4 16 cells/μL) and started on B/F/ TAF Passarelli et al. 75 M Hypertension, deceased donor Died on day 18 • Presented with cough and progressive dyspnea × kidney transplant 3 years ago 4 days with SARS-CoV-2 detected upon admission (tacrolimus 4 mg/day and • Chest CT revealed bilateral ground-glass opacities prednisone 5 mg/day), cirrhosis for which ceftriaxone and clindamycin were started while prednisone was increased to 30 mg/day and tacrolimus was discontinued • After 4 days, required mechanical ventilation and started on IV hydrocortisone 50 mg every 6 h • Developed septic shock on day 12 despite treatment with meropenem, vancomycin, and fluconazole • C. neoformans isolated from blood cultures on day 12 and 16 Woldie et al. 24 M Autoimmune hemolytic anemia • Presented with fevers, myalgias, cough with SARS- Died prior to (prednisone 20 mg/day) CoV-2 detected upon admission identification of • His prednisone dose was increased to 1.5 mg/kg/ cryptococcosis day and cyclophosphamide 50 mg every 12 h was started • Discharged after 13 days, but readmitted 1 week later due to persistent headache which then progressed to decreased consciousness and new onset seizures • MRI brain revealed necrotizing encephalitis for which IV methylprednisolone 1 g/day and IVIG 1 g/kg were initiated • Sustained a cardiac arrest prior to undergoing LP • C. neoformans was isolated from blood cultures obtained on the second hospitalization (Continued) DB Chastain, AF Henao-Martínez et al. journals.sagepub.com/home/tai 5 Table 1. (Continued) Case Age (years) Sex Medical, surgical, or social history Clinical course Outcome Cafardi et al. 78 M Hypertension, COPD • Presented with fever, myalgia, hypoxia, dyspnea, Died approximately headache, and diarrhea with SARS-CoV-2 detected 20 days after upon admission identification of • Remdesivir × 5 days, IV methylprednisolone 40 mg cryptococcosis every 12 h, and inhaled recombinant sialidase × 10 days were initiated • After 16 days, clinically improved but then deteriorated with onset of fevers and respiratory failure requiring mechanical ventilation and bronchoscopy • C. neoformans was isolated from respiratory cultures, whereas serum CrAg was not detected • Received LAMB × 6 days but sustained AKI and was transitioned to isavuconazole Ghanem and 73 F R THA 2 weeks prior to admission, • Febrile and hypoxic with patchy bilateral infiltrates Discharged to Sivasubramanian otherwise unremarkable on CXR postoperatively a rehabilitation • SARS-CoV-2 detected and received azithromycin × 5 facility days and dexamethasone × 10 days • After 7 days of therapy, developed new onset gait instability, falls, and aphasia with CT head demonstrating hydrocephalus • Underwent EVD placement and CSF analysis revealed 25 WBC/μL, 173 mg/dL protein, and <10 mg/dL glucose • C. neoformans isolated from CSF cultures and treated with amphotericin and flucytosine Khatib et al. 60 M Hypertension, diabetes mellitus, • Required ICU admission and MV due to COVID-19, Died 10 days after ischemic heart disease received three doses of tocilizumab, multiple doses identification of of methylprednisolone, and hydrocortisone cryptococcosis • Required HD for AKI • Developed candidemia (Candida parapsilosis) and received anidulafungin • C. neoformans isolated from blood cultures while receiving anidulafungin so switched to amphotericin and flucytosine (Continued) Therapeutic Advances in Infectious Disease 9 6 journals.sagepub.com/home/tai Table 1. (Continued) Case Age (years) Sex Medical, surgical, or social history Clinical course Outcome Thota et al. 76 F Hypertension, osteoarthritis, • Presented with diarrhea, confusion, and weakness Discharged to gastroesophageal reflux disease with SARS-CoV-2 detected upon admission LTCF but remained • Cefepime, ampicillin, vancomycin, and IV comatose methylprednisolone 40 mg every 12 h were initiated due to fevers and lactic acidosis • On day 3, required mechanical ventilation and then received convalescent plasma, remdesivir, tocilizumab, and inhaled budesonide • Clinically improved and discharged to a SNF, but readmitted with fever and encephalopathy after 14 days • MRI brain demonstrated numerous acute and subacute infarcts in the cerebral and cerebellar hemispheres without enhancement • CSF analysis revealed 87 WBC/μL, 3530 RBC/μL, 193 mg/dL protein, and <5 mg/dL glucose, and CrAg titer > 1:2560 • C. neoformans was isolated from CSF and blood cultures and treated with amphotericin and flucytosine × 3 weeks • Transitioned to fluconazole after CSF sterilized Thyagarajan et al. 75 M Diabetes mellitus, hypertension, • Presented with fever and difficulty breathing with Died prior to obesity, osteoarthritis SARS-CoV-2 detected upon admission requiring identification of ICU admission and MV cryptococcosis • Remdesivir × 5 days, IV dexamethasone 6 mg daily × 10 days, and convalescent plasma • Developed VAP due to MRSA on day 17 and was treated with vancomycin then linezolid • Continued to clinically deteriorate and was transitioned to comfort measures • C. neoformans isolated from blood cultures on day 26 A phase III randomized placebo-controlled study to examine the efficacy and safety of DAS181 for the treatment of lower respiratory tract parainfluenza infection in immunocompromised subjects (https://clinicaltrials.gov/ct2/show/NCT03808922). AKI, acute kidney injury; B/F/TAF, bictegravir/emtricitabine/tenofovir alafenamide; CrAg, cryptococcal antigen; CSF, cerebrospinal fluid; CT, computed tomography; CXR, chest radiography; EVD, external ventricular drain; F, female; HD, hemodialysis; ICU, intensive care unit; IV, intravenous; LAMB, liposomal amphotericin B; LP, lumbar puncture; LTCF, long term care facility; M, male; MRSA, methicillin resistant Staphylococcus aureus; MV, mechanical ventilation; R, right; RBC, red blood cell; SNF, skilled nursing facility; THA, total hip arthroplasty; VAP, ventilator acquired pneumonia; VL, viral load; WBC, white blood cell. DB Chastain, AF Henao-Martínez et al. transplantation. Characterization of symptoms necessary for reactivation, which in this case caused by cryptococcosis was challenging due to include SARS-CoV-2 infection–induced lympho- overlap with COVID-19. However, due to low penia combined with prolonged high-dose corti- suspicion for cryptococcosis many patients clini- costeroid treatment. Mechanisms to predict and cally deteriorated, some of which died prior to prevent reactivation of latent cryptococcosis are detection of cryptococcosis. needed given the increasing incidence of immu- nosuppressive diseases and widespread use of During hospitalization, 25% of patients received immunosuppressive medications. tocilizumab, and 88% received corticosteroids. In the only case where corticosteroids were not Asymptomatic treatment-naïve PLH with CD4 administered for COVID-19, diagnosis of crypto- cell counts ⩽100 to 200 cells/µL undergo screen- coccosis subsequently led to a new diagnosis of ing for cryptococcosis using serum cryptococcal 24 32,33 HIV, whereas C. neoformans was most commonly antigen (CrAg) testing. Among those with identified after receiving immunomodulatory ther- detectable CrAg, CSF should be evaluated to apy in all other cases; C. neoformans was isolated determine whether the cryptococci have dissemi- from blood cultures in 63% (n = 5) of patients. Of nated to the central nervous system (CNS). Early the 38% (n = 3) of patients who underwent cere- identification and treatment of cryptococcus in brospinal fluid (CSF) evaluation, C. neoformans PLH with low CD4 cell counts has led to was detected in all CSF cultures. Overall mortality decreased mortality attributable to cryptococcal 34–36 was 63%, of which two patients died before identi- meningoencephalitis. Unfortunately, similar 27,28 fication of cryptococcosis. recommendations to detect cryptococcal antigen- emia and ultimately identify localized pulmonary 22,23,29 In four cases, including our patient, no tra- cryptococcosis or disseminated cryptococcosis do ditional risk factors for cryptococcosis were iden- not exist in HIV-uninfected immunodeficient tified. Notably, our patient had a glycated patients nor immunocompetent patients. hemoglobin (A1C) of 5.6% (A1C ⩾ 6.5% diag- Diagnosis of cryptococcosis in non-HIV non- nostic for diabetes), but did not undergo HIV transplant patients is often missed or significantly testing. While viral pneumonia increases the risk delayed compared to PLH or organ transplant 37,38 of invasive fungal infections, it remains unclear recipients resulting in lower survival rates, as whether SARS-CoV-2 infection, immunomodu- the sensitivity of CrAg LFA to detect CrAg in latory therapy, or a combination of both were serum, while still relatively high, is lower than responsible for increased susceptibility to acute that in PLH. Unfortunately, the sensitivity of infection with or reactivation of C. neoformans in serum CrAg is unknown in COVID-19 patients these patients with COVID-19. Although much with an impaired immune response. As such, the of the pathogenesis of cryptococcosis in COVID- risk of dissemination is increased compared to 19 patients is poorly defined due to limited details immunocompetent patients, therefore necessitat- in other case reports, we suspect our patient had ing an evaluation for meningoencephalitis in latent cryptococcosis which reactivated because COVID-19 patients with serologic or microbio- of SARS-CoV-2 infection–induced lymphopenia logic evidence of cryptococcosis. and corticosteroid treatment. Blood cultures obtained on admission at the OSH were sterile. An optimal treatment regimen for cryptococcosis Based on a rat model of pulmonary cryptococco- has not been identified in non-HIV nontransplant 40,41 sis which mirrors human infection, C. neoformans patients due to limited data. As a result, most persists as a granuloma within the lung despite treatment regimens are based on efficacy data from 17,21 initial containment and no clinical symptoms. PLH and SOT recipients, but depend on the extent Following receipt of corticosteroid therapy, of disease. A combination of lipid-associated formu- increased fungal burden and extrapulmonary dis- lations of amphotericin B (LFAB), such as liposo- semination were observed to a greater extent mal amphotericin B (LAmB) or amphotericin B when corticosteroid therapy was administered lipid complex (ABLC), plus flucytosine is most within 4 weeks of initial infection with C. neofor- effective due to rapid fungicidal activity and is con- mans. However, similar findings were not sidered first line for induction therapy among observed with late stages of latent cryptococcosis patients with meningoencephalitis, disseminated suggesting multiple mechanisms might be (e.g. involvement of two or more noncontiguous journals.sagepub.com/home/tai 7 Therapeutic Advances in Infectious Disease 9 sites), or severe pulmonary disease (e.g. diffuse pul- therapy, most often a combination of LFAB plus monary infiltrates). In cases of meningoencephalitis, flucytosine, thereby halting or eliminating further antifungal therapy should be combined with daily dissemination and improve overall mortality. therapeutic lumbar punctures or placement of a lumbar drain or ventriculostomy to reduce intracra- Author contributions nial pressure (ICP). Indeed, most patients who were Daniel B. Chastain: Conceptualization; Data still alive after identification of cryptococcosis curation; Visualization; Writing – original draft; received an LFAB in combination with flucyto- Writing – review & editing. 23–25,29 sine, though few patients underwent CSF Andrés F. Henao-Martínez: Conceptualization; 23,24,29 examination. Supervision; Writing – review & editing. Austin C. Dykes: Writing – original draft; While LFABs are preferred due to lower risk of Writing – review & editing. nephrotoxicity, amphotericin b deoxycholate Gregory M. Steele: Writing – review & editing. (AmBd) can be used if LAmB or ABLC are una- Laura Leigh G. Stoudenmire: Writing – review vailable. Many resource-limited countries are & editing. unable to access flucytosine due to limited availa- Geren M. Thomas: Writing – review & editing. 43,44 bility and prohibitive costs, requiring use of Vanessa Kung: Writing – review & editing. less efficacious regimens such as high dose flucon- Carlos Franco-Paredes: Conceptualization; 40,41 azole with or without AmBd. A prolonged Supervision; Writing – review & editing. duration of induction therapy of 4 weeks, or longer in the presence of neurologic complications, is Conflict of interest statement required in non-HIV nontransplant patients. After The authors declared no potential conflicts of clinical improvement with induction therapy, flu- interest with respect to the research, authorship, conazole 800 mg per day should be initiated as and/or publication of this article. consolidation therapy for at least 8 weeks followed by 200 to 400 mg per day as maintenance therapy Funding for at least 1 year. However, the duration of anti- The authors received no financial support for the fungal therapy is somewhat dependent on resolu- research, authorship, and/or publication of this tion of the underlying immunodeficiency allowing article. for gradual restoration of immune function. Ethics approval Our report did not require ethical board approval Conclusion as it described the treatment of a single patient Cases of cryptococcosis have previously been which does not meet the federal definition of reported following short- or long-term initiation of human subjects research. This case was docu- corticosteroids, IL-6 inhibitors, and JAK inhibitors mented in the context of routine care and the for patients with autoimmune diseases, but it information presented was anonymized in accord- remains unknown how the use of one or a combi- ance with the Declaration of Helsinki. nation of these therapies will directly or indirectly alter immunologic response in patients with Patient consent COVID-19. Clinicians must be suspicious of cryp- Consent was unable to be obtained as the patient tococcosis in COVID-19 patients who clinically is deceased and their relatives were not contacta- deteriorate following treatment with immunomod- ble. As such, details have been removed from the ulatory therapies as signs and symptoms of crypto- case description to ensure anonymity. coccosis may overlap with COVID-19. Given the utility of CrAg LFA to detect CrAg in serum cou- ORCID iDs pled with the high rate of missed opportunities to Daniel B. Chastain https://orcid.org/0000- identify cryptococcosis and dire outcomes in non- 0002-4018-0195 HIV nontransplant patients, early recognition, Andrés F. Henao-Martínez https://orcid.org/ perhaps through the use of a CrAg screen-and- 0000-0001-7363-8652 treat strategy, prior to administration of immu- nomodulatory therapies in COVID-19 patients Carlos Franco-Paredes https://orcid.org/ will result in prompt administration of antifungal 0000-0001-8757-643X 8 journals.sagepub.com/home/tai DB Chastain, AF Henao-Martínez et al. 11. Rodriguez-Morales AJ, Sah R, Millan-Oñate J, References et al. COVID-19 associated mucormycosis: the 1. Giamarellos-Bourboulis EJ, Netea MG, Rovina urgent need to reconsider the indiscriminate use N, et al. Complex immune dysregulation in of immunosuppressive drugs. Ther Adv Infect COVID-19 patients with severe respiratory Dis. Epub ahead of print 18 June 2021. DOI: failure. Cell Host Microbe 2020; 27: 992–1000.e3. 10.1177/20499361211027065. 2. NIH. COVID-19 treatment guidelines panel. 12. Salehi M, Ahmadikia K, Badali H, et al. 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Published: Jan 1, 2022

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