COVID-19-associated fungal spectrum: The intraoral purview

INTRODUCTION

Since 2019, the world has been battling a devastating pandemic in the form of COVID-19 infection, which has afflicted more than 170 million people and has led to 3.6 million deaths worldwide.^[1] Dealing with the novel severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection was dwelling into an unexplored universe with limited knowledge about disease presentation, the possibility of rapid and frequent viral mutations, an individual’s immune response, as well as in the context of the resources available in the prevailing health-care system. With this finite understanding, India entered the catastrophic second wave that witnessed numerous COVID-19 patients being managed with diverse treatment protocols which included multivitamins, antiparasitics, systemic corticosteroids, and injectable antivirals (Remdesivir). Several cases of severe COVID-19 required administration of oxygen, hospitalization, prolonged stay in ICU, and mechanical ventilator support.

The immune dysregulation triggered by SARS-CoV-2 along with the already prevalent immunosuppressive states such as diabetes mellitus, hematological malignancies, lung diseases, and the concurrent administration of immunosuppressive corticosteroid therapy served as a causal pathway for the initiation and progression of other opportunistic infections dominated by ones of fungal origin.^[2] The exact etiology of COVID-19-associated fungal spectrum (CAFS) is yet to be realized. However, with various fungal infections being declared as an epidemic in India, the critical reality demands urgency for special focus on different aspects of CAFS.

AN INSIGHT INTO CAFS

CAFS encompasses Aspergillus, Candida, Mucor, Coccidioides, Cryptococcus, Pneumocystis, and Saccharomyces. The fungal coinfections linked with COVID-19 remain to be largely missed or misdiagnosed. Interestingly, the fungi that commonly colonize the respiratory tract and oropharyngeal mucous membrane have been most regularly associated with COVID-19 infection, namely, Mucor, Aspergillus, and Candida.^[3] Moreover, the treatment of these possibly fatal infections has become an additional burden to the already stressed health-care system. The mycological conditions have varied intraoral presentation ranging from superficial to deep fungal infections of the oral tissues. Hence, a dental professional can play a key role in the early diagnosis and prompt management of fungal infections, thereby, reducing the mortality rate significantly. The present perspective is to summarize the fungal infections reported in COVID-19 patients.

COVID-19 AND MUCOR

Mucormycosis is the fungal infection caused by fungi of Mucorales order; genus Mucor, Rhizopus, Rhizomucor, and Absidia in Zygomycetes class. Immunosuppression caused due to COVID-19 infection leads to a reduction in the number of circulating CD4 T and CD8 T cells and an overwhelming inflammatory response that renders the body weak and susceptible to infections. This is aggravated by the immune suppressing effects of underlying conditions especially diabetes and use of steroids. Other factors such as humid climate and high temperature also provide a conducive environment for the growth of these fungi, leading to an increased risk of these infections.^[4]

During the second wave of COVID-19, India has seen an increase in the incidence of rhino-orbitocerebral mucormycosis in patients suffering from COVID-19 or recovering from the infection.^[5,6] Recently, in May 2021, the Health Ministry of India urged the state governments to declare the mucormycosis infection also known as black fungus, as a notifiable disease. Following this advisory, many Indian states and union territories have declared mucormycosis as an epidemic among which Rajasthan was the first state to declare mucormycosis epidemic on May 19, 2021.^[7]

COVID-19 AND ASPERGILLUS

Spores of Aspergillus are typically present everywhere around us, hence, can be inhaled easily and subsequently enter the human lung tissues and/or paranasal sinuses causing local to disseminated aspergillosis. They are known to cause life-threatening invasive aspergillosis in immunocompromised individuals with bone marrow transplantations or hematological malignancies. The species causing invasive aspergillosis (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus) have 30–95% mortality rate even if diagnosed early and despite appropriate antifungal treatment.^[14]

As reported by Lei et al. in China, patients with severe COVID-19 had high rates of positive galactomannan, thereby increasing the probability of concomitant fungal infection.^[15] Furthermore, patients with COVID-19 have presented with high serum levels of pro-inflammatory cytokines such as interleukin (IL)-6 and IL-10. Following an increase in IL-10 levels, greater Th2 response and Th1 immune depression are seen which increase host susceptibility to lethal Aspergillus infection. IL-6 plays an important role in protective immunity against Aspergillus. Immunomodulatory treatment with tocilizumab which has been approved in patients with severe COVID-19 as an anti-IL-6 agent can, nevertheless, potentially cause Aspergillus infection by reducing IL-6 immune response.^[16] In the study by Bartoletti et al., most patients received anti-IL-6 treatment with tocilizumab as well as corticosteroids.^[17]

COVID-19 AND CANDIDA

Candida albicans is a common resident of the oral mucosa, however, its growth is suppressed by other organism in the oral microbiome, thus, remaining non-virulent. Species such as Candida tropicalis, Candida glabrata, Candida krusei, and Candida parapsilosis are found at various mucosal surfaces, such as the skin and the pulmonary, gastrointestinal, and urinary tracts.^[20,21] A literature of 11 cases by Moser et al. reported upregulated monocyte CD80 and negate release of IL-6 and IL-1α, thus increasing the susceptibility for candidemia in critically ill COVID-19 patients.^[22] India reports the rate of superficial and invasive candidiasis to be 2.5% in the first wave.^[23] Researchers support the concept of classical risk factors such as prolonged ICU hospitalization, central venous catheters, and broad-spectrum antibiotic use^[24] for invasive candidiasis despite the marked immune cell dysregulation seen in COVID-19 patient.^[25]

OTHER FUNGAL INFECTIONS ASSOCIATED WITH COVID-19

Although not diagnosed in India yet, there are other fungal organisms reportedly associated with COVID-19. Coccidioidomycosis and COVID-19 coinfection have been reported in Southwest United States, both diseases having common symptoms that include fever, dry cough, dyspnea, myalgia, and headache. Infection with COVID-19 might reactivate Coccidioides fungus which remains in the lung in a latent state. This has been seen in certain conditions such as pregnancy or immunocompromised states.^[29]

Histoplasmosis and Cryptococcus are seen as opportunistic fungal coinfections in COVID-19 patients with AIDS and immunosuppression. Histoplasmosis capsulatum causes Histoplasmosis infection which is a deep fungal infection affecting pulmonary tissue or mucocutaneous areas. Mucocutaneous form may produce solitary, painful or painless, ulcerative, erosive lesions on the tongue, palate, and/or buccal mucosa. Oral ulcerations are typically characterized by firm rolled borders that mimic a malignant neoplasm.^[30]

Cryptococcemia caused by Cryptococcus neoformans, a known cause of meningoencephalitis in immunocompromised patients, has been reported in COVID-19 patients with a history of receiving tocilizumab and corticosteroids.^[31]

Cases of Saccharomyces cerevisiae have been reported in a few COVID-19 patients hospitalized in ICU, who have taken probiotics containing Saccharomyces. These infections are often misdiagnosed as Candida infections.^[32]

Pneumocystis pneumonia, mostly seen as an opportunistic fungal infection in AIDS patients, was reported as a coinfection in a patient with COVID-19 but with no known immunodeficiency or risk factors for the development of Pneumocystis jirovecii infection.^[33]

CONCLUSION

There is enough evidence to suggest that COVID-19 infection causes immunosuppression, hence, increasing the susceptibility of developing opportunistic fungal infections. India has reported multiple cases of such fungal infections as post-COVID complications, often nicknamed as white fungus (Candida), black fungus (mucormycosis), and yellow fungus (aspergillosis). The development of these diseases may be attributed to the use of glucocorticoids, and hence, judicious use of these drugs has been suggested. Further, in the absence of a clear benefit, drugs targeting immune pathways such as tocilizumab should be discouraged.

The stewardship in managing COVID-19 patients needs to focus on expanding knowledge about the risk factors associated with the development of opportunistic fungal infections. Early diagnosis and timely management of these infections can improve patient outcomes significantly. These infections have proven to be fatal, and thus, it is important to be vigilant about opportunistic fungal pathogens and robust surveillance of high-risk hosts is required to reduce the number of these infections.