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Accelerated Progression of Disseminated Coccidioidomycosis Following SARS-CoV-2 Infection: A Case Report

ABSTRACT We describe a patient with subclinical coccidioidomycosis who experienced rapid disease dissemination shortly after SARS-CoV-2 infection, suggesting host immune response dysregulation to coccidioidomycosis by SARS-CoV-2. We hypothesize that disrupted cell-mediated signaling may result after SARS-CoV-2 infection leading to functional exhaustion and CD8+ T-cell senescence with impairment in host cellular response to Coccidioides infection.

SARS-CoV-2 is the novel zoonotic beta-coronavirus responsible for the ongoing COVID-19 pandemic, and our related understanding of host immunology is rapidly developing. In COVID-19, both impairment and hyperactivation of the immune system may occur 7 with a wide spectrum of host responses. SARS-CoV-2 infects the human respiratory tract by its spike (S) protein binding to the host human angiotensinconverting enzyme receptor 2 (h-ACE2). 8 Following endocytosis, inflammatory pathways, including the expression of NF-kappa B, are activated, leading to numerous cellular responses. 9 Th1 and cytotoxic T-cells are activated by macrophages with varied degrees of cytokine release which may be predictive of the degree of disease incurred after SARS-CoV-2 infection. 10 Among activated CD8+ T-cells in COVID-19, there is increased expression CD57, a described marker of cellular senescence, as well as decreased potential for proliferation. 11

CASE
A previously healthy 23-year-old African American man, originally from New York City, had been serving in the U.S. Navy at Naval Air Station Lemoore (NASL) in the San Joaquin Valley of California. He was deployed onboard the USS Theodore Roosevelt during that ship's COVID -19 outbreak. 12 During the outbreak, day 0, he developed a mild febrile illness and tested positive for SARS-CoV-2 by nasopharyngeal swab polymerase chain reaction testing; he had no associated respiratory symptoms, and his infection resolved without need for further medical care. During this time, he was ashore on the island of Guam and had been away from NASL at sea for 3 months.
On day 30, he was hospitalized in Guam following an episode of presyncope. Upon admission, he reported 21 days of drenching night sweats, 14 kg of unintentional weight loss, bony pain, and non-tender ulcers over his right shoulder. Physical examination revealed generalized lymphadenopathy; laboratory testing demonstrated leukocytosis (17 x 10 9 cells/L) with marked eosinophilia (33%). Computed tomography (CT) of his chest demonstrated diffuse sub-centimeter ground-glass opacities with mediastinal, hilar, and right axillary lymphadenopathy and centrilobular nodules along with widespread lesions throughout the axial and appendicular skeleton. Because of concern for malignancy, he was transported from Guam to San Diego for further radiographic staging and evaluation on day 33.
In San Diego, positron emission tomography re-demonstrated the initial CT findings with avid fluorodeoxyglucose uptake in the associated areas (Fig. 1A). A core needle biopsy of a right axillary lymph node demonstrated granulomatous lymphadenitis with fungal yeast elements. Skin biopsies of his right shoulder lesions demonstrated rare, thick-walled spherules with multinucleated giant cells and eosinophils consistent with Coccidioides ( Fig. 1B-C). Serologic testing for anti-Coccidioides IgG and IgM was positive, with a complement fixation titer of 1:64. There was no evidence of central nervous system involvement based on cerebral spinal fluid analysis. Given extensive axial skeletal involvement, the patient was started on induction therapy with intravenous liposomal amphotericin B 5 mg/kg daily, but it was stopped after 14 days (54 days since initial COVID-19 diagnosis) because of drug-induced liver injury. He was transitioned to therapy with oral itraconazole 200 mg twice daily and has had continued clinical improvement.

DISCUSSION
Cellular immunity to Coccidioides infection requires both coordinated and sustained Th1 and cytotoxic T-cell response, 3 possibly with emphasis on the later. 6 In host defense against SARS-CoV-2, CD8+ T-cells are described as central for clearance and recovery. 13 SARS-CoV-2 undergoes endocytosis upon binding to the h-ACE2 receptors in the respiratory tract, with subsequent mast cell production of IL-4 9 which is necessary for activation of cellular immune response. As of present, Th1 and cytotoxic T-cell responses are believed to be essential for host defense in COVID-19. 14 However, an impairment and reduction of cytotoxic CD8+ T-cells are also observed 11 and described to undergo "functional exhaustion" 11,15 after SARS-CoV-2 infection.
Our patient had no significant symptoms because of Coccidioides during the months at sea preceding the COVID-19 outbreak. This is common, as a majority of cases of coccidioidomycosis are subclinical with spontaneous resolution. 1 We posit that his initially subclinical infection was worsened by SARS-CoV-2-mediated immunosuppression. Although Coccidioides infection has been described during the management of COVID-19 before, 16 it is recognized that our patient may have had two unrelated primary infectious processes occurring simultaneously. This is improbable: coccidioidomycosis is not a contagious disease between humans, and Coccidioides is not endemic in Guam, with his only potential location for infection having been in California before deployment. Additionally, although disseminated coccidioidomycosis occurs in a minority of infected patients, such rapid dissemination occurring months following primary infection is extremely rare in otherwiseimmunocompetent patients. 17 We hypothesize that patients infected with SARS-CoV-2 may experience diminished cellmediated signaling as a consequence of functional exhaustion and CD8+ T-cell senescence with consequential impairment in cellular response to Coccidioides infection. Further investigation should be pursued in patients with coccidioidomycosis and newly diagnosed COVID-19 with attention to monitoring CD57 levels among CD8+ T-cells. Doing so could characterize a unique clinical relevance of cellular senescence in COVID-19 immunology. In the ongoing COVID-19 pandemic, this may have significant ramifications for not only persons exposed to Coccidioides, but potentially as well as with other infectious diseases dependent on CD8+ T-cell function for host protection.

ACKNOWLEDGMENTS
We would like to thank Dr. Julia H. Cheringal and Dr. Robert L. Fenequito of U.S. Naval Hospital.

FUNDING
No funding was utilized for this work.