Correspondence Address:
K Devaraja
Department of Otorhinolaryngology and Head and Neck Surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
India

Full Text



Sir,

Mucormycosis is an invasive fungal infection with considerable morbidity and mortality.[1] It is primarily seen in patients with poorly controlled diabetes mellitus or other immunocompromised conditions.[1] During the second wave of the COVID-19 pandemic, India witnessed a sharp rise in the number of mucormycosis cases, mostly in active or recovered patients of COVID-19 infection.[2] While there is still a debate on reasons for the recent surge in COVID-19-associated mucormycosis (CAM), this letter briefly discusses a few crucial etiopathological peculiarities of CAM and its management principles.

According to the traditional model of disease causation, a disease process is a culmination of a complex interplay between the agent-, host-, and environment-related factors. This model of the epidemiological triad can probably best explain the etiopathology of CAM. As for the etiological agent of CAM is concerned, just like in mucormycosis cases before the COVID-19 pandemic, a group of fungi belonging to the Zygomycota family, are held responsible for CAM.[1],[2] These fungi are omnipresent in the environment and can produce invasive infection when inhaled or inoculated into the skin or mucosal tract, but only in susceptible individuals. From the host's susceptibility point of view, the available evidence points toward the diabetes mellitus as a critical risk factor for CAM, which happens to be a well-known risk factor even for the mucormycosis in non-COVID individuals.[2],[3],[4] This is not surprising considering that the studies have already shown that the fungi responsible for mucormycosis thrive in hyperglycemic situations. On the other hand, the therapeutic use of corticosteroid during COVID care is reported to be another independent risk factor for CAM.[2],[3],[4] The systemic steroids not only derange the blood sugar control in a known diabetic or a prediabetic but also suppress the protective immune response against the fungal infection facilitating tissue invasion by the latter. Interestingly, some of the studies have reported a strong association between the CAM and severe COVID-19 infection, suggesting an active role of the viral infection itself in increasing the susceptibility to CAM.[3],[4] However, systemic steroid use is a potential confounding factor in these reports, as almost all of the severe COVID-19 infection cases would have received steroid therapy for respiratory failure, which would have contributed to increased risk of subsequent CAM among these study cohorts. Nevertheless, the effect of viral infection on an individual's susceptibility to CAM cannot be downplayed completely, as up to one-third of the affected patients may not have any other immunosuppressive comorbidities other than COVID-19 infection itself.[5] Regarding the environmental factors, use of contaminated humidifying filters or other medical equipment, contaminated oxygen source, ventilator dependence, and even unwashed or moist masks that could harbor fungal spores, have been speculated to have contributory role in CAM. However, at this stage, there is no corroborative evidence to support the etiological role of any of these factors in CAM.

The average time duration between the COVID-19 infection and the diagnosis of CAM in susceptible individuals is reported to be around 2 weeks.[4] Most of the CAM patients present with predominant sinonasal manifestations, followed by features of orbital involvement.[2],[3],[4] In a patient with sinonasal symptomology, the presence of an ulcerative lesion or a focal area of discoloration over the mucosa of the nasal cavity or hard palate is the tell-tale sign of mucormycosis. Similarly, crusts inside the nasal cavity or features suggestive of orbital cellulitis, facial cellulitis, and focal neurological deficits should be taken as mucormycosis unless otherwise proven. Although the signs and symptoms may be nonspecific and trivial in the initial stages, the threshold for further evaluation should be kept low among the high-risk group, particularly among the patients with diabetes mellitus or other immunosuppressive conditions, who have (or had) COVID-19 infection, with or without steroid therapy. Wet mount microscopy or fungal staining of the clinical material might help establish the rapid diagnosis of CAM, and cross-sectional imaging, preferably magnetic resonance imaging, could provide a detailed assessment of the extent of the disease.

The management principles of CAM do not differ significantly from those of the non-COVID mucormycosis. Tackling a case of mucormycosis needs a multidisciplinary approach, with the participation of experts from otorhinolaryngology, ophthalmology, microbiology, radiology, general medicine, and infectious diseases. The critical components of managing mucormycosis are surgical debridement, antifungal therapy, and control of underlying comorbidities. The therapeutic success in any given CAM case depends on how effectively these three parallel arms of treatment are executed. One of the crucial parts of management in CAM is early and adequate surgical debridement. The objectives (or the benefits) of surgical intervention in mucormycosis are three-fold. First, it helps in confirming the diagnosis by providing the tissue for microbiological and pathological assessment. Second, the clearance of dead and devitalized tissue reduces the fungal load significantly, and the improved vascularity at the surgical site enables the adequate reach of systemic antifungal agents to the active zones of invasive disease. Finally, the surgically opened drainage pathways of the paranasal sinuses facilitate the clearance of retained secretion, thus reducing the chances of secondary bacterial infection and corresponding inflammatory response. In the majority of the CAM cases, these objectives can be achieved by an endoscopic debridement of the involved tissue inside the nose, paranasal sinuses and orbit, but some of the extensive cases may mandate an open approach and even an orbital exenteration.[2],[3],[4] With regards to antifungal therapy for CAM, systemic amphotericin B, as liposomal formulation, is the most preferred antifungal agent over the others, due to its superior activity against the fungi causing mucormycosis.[1],[4],[5] During the recent outbreak of CAM, there was a period of an acute scarcity of liposomal preparation of amphotericin B, prompting the clinicians to use either of the emulsified and deoxycholate forms. The deoxycholate amphotericin B is known to be an effective alternative to liposomal amphotericin B, but has increased risk of renal toxicity, which is mostly transient in nature.[6] The use of nonliposomal formulations of amphotericin B necessitates more vigilance for its toxicity and may require more time to reach the desired cumulative dose of the antifungal agent. Some authors have tried amphotericin B as a topical application to the sinuses or as retrobulbar or intravitreal injections, but the efficacy of these approaches remains to be established.[4] Last but not least, underlying diabetes should be brought into control for optimizing the therapeutic outcome, as the persisting elevation of blood sugar levels is one of the poor prognostic factors for survival in CAM.[4] During the ongoing medical management, along with the regular monitoring of blood sugar levels and the markers of toxicity, the treating team should also be vigilant about the possible progression of the fungal disease and should manage it accordingly. As mentioned earlier, poorly controlled blood sugar levels, intracranial extension, stay in the intensive care unit are some of the poor prognostic factors in CAM.[5] Furthermore, early recognition, timely intervention, and adequate antifungal medications are supposed to increase the chances of therapeutic success in CAM.

To summarize, for achieving the optimal outcome, the medical fraternity, as well as the patient community, must be sensitized about the risk factors and manifestations of the CAM. Although the CAM has some etiopathological peculiarities, its management principle does not differ from the non-COVID era and involves a three-way approach consisting of adequate amphotericin B, control of the underlying comorbidity and debridement of the devitalized tissue, i.e., ABCD.

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