The nation had already been struggling with the notorious second wave of COVID-19 infection when the epidemic of mucormycosis presented as another hurdle to tackle with. The average annual incidence of non covid assosciated mucormycosis in the past 5 years presenting to our department was 8.9 cases per year. Our study comes as the largest prospective institutional study studying the sudden surge of mucormycosis, with 35 COVID assosciated mucormycosis cases till date.
Mucormycosis is commonly known to be an opportunistic, angio-invasive opportunistic fungal infection that infects people predisposed with uncontrolled diabetes mellitus, prolonged steroid usage or immunosuppressive therapy, malignancies, primary or secondary immunodeficient state like in HIV infection, tuberculosis, lung diseases, chronic malnutrition, renal failure, etc. (7) The hypoxic state produced in COVID infection along with high glucose and ferritin levels and low phagocytic action of leucocytes and the management of the infection with steroid and other immunosuppressive drug therapies like remdesivir make the environment conducive for mucor infection.(6)
In our study, majority of ROCM affected patients were middle aged men with mean age group of 40.45± 6 years, a decade younger than in the latest largest retrospective study (COSMIC report) conducted by Sen M et al(9), where the mean age was 51.9 (range 12–88) years with a male preponderance of 71%.,where they quote greater severity of COVID-19 in male gender and greater outdoor exposure and, thus, to fungal spores as the possible reasons for this majority. The major highlight that came forward in our study was that CAM did not affect healthy individuals and all the people affected were predisposed to the disease, with the most common risk factors being steroid usage and uncontrolled diabetes. Out of the 35 patients enrolled, 51.4% had history of steroid intake and 65.7% had diabetes mellitus. These findings are consistent with a systematic review conducted by John et al in 41 confirmed cases of CAM where 93% were diabetics and 88% had a history of corticosteroid intake. (10) Moorthy et al (11) recently reported the association of COVID-19 infection with uncontrolled DM and usage of corticosteroids. Furthermore, the incidence of mucormycosis, in our study, was more in people with mild to moderate covid who were managed under home isolation with unregulated or self-prescribed use of steroid, with average duration of treatment lasting > 2weeks. This led to upstaging of the disease to severe covid and resultant hospitalization in 65.8% of cases where oxygen supplementation and steroid therapy became the key management. In the pre COVID era, diabetes mellitus has been identified as an independent risk factor for mucormycosis (1, 4) as has been prolonged ( >3 weeks) of high-dose systemic corticosteroid (9); however, there is paucity of literature to state a causal effect relationship with reference to oxygen supplementation, steroid and immunosuppressive drug therapy in covid-19 patients.
The mode of infection of mucor is usually by inhalation of fungal sporangiospores in the paranasal sinus which upon germination, actively spread into the adjacent spaces-inferiorly to palate, posteriorly to sphenoid sinus, laterally to the cavernous sinus and orbit, and cranially to the brain through orbital apex or cribriform fossa. (12, 13) Most of the patients that presented to us were ROCM stage 3 or beyond at the time of first presentation. It might be due to relatively late presentation for the primary ophthalmic symptoms of the disease entity when fungus has further spread beyond the paranasal sinus and orbit. The onset of first symptom suggestive of mucormycosis was, 70% of the times, within 6 weeks of recovery from covid infection, the median time duration being 21.5 days from the day of negative RT-PCR report. Our study determined orbital/facial swelling as the most common presenting feature followed by orbital/facial pain, orbital/facial discoloration, dental pain, and ptosis. The most common presenting signs were periocular/facial edema followed by ptosis, periocular/facial discolouration, and hypoesthesia. These primary signs and symptoms of covid 19 associated ROCM were largely consistent with that of pre covid era ROCM. (14)
The gold standard for definite diagnosis of ROCM still remains histopathological analysis of mucosal biopsy. (8). In our study, samples from nasal mucosa, paranasal sinus mucosa or orbital tissue was subjected to routine fixed sections for histopathological analysis with Hematoxylin-eosin, periodic acid-schiff, and/or Grocott-Gomori’s methenamine silver special strain. Identification of broad non-septate or sparsely septate fungal hyphae with associated tissue damage/ angioinvasion/ necrosis was characteristic of the disease. Contrast enhanced MRI has been proved to be a superior imaging technique over Contrast enhanced CT. (9) MRI was the preferred modality to monitor the extent of the disease The latest retrospective series on CAM from a geographically different location published by T.V. Dave et al (15) analysed 58 cases and noted that Intracranial extension was seen in 33%, comparable to 22.85% in current study. (p = 0.2). In the COSMIC report, diffuse orbital involvement predominated in 40% followed by involvement of the medial orbit in 27%, compared to medial orbital wall involvement as the most common form of orbital involvement (33%) in our study. In the CNS, cavernous sinus was most commonly involved in both the studies (53% and 75% respectively). Besides diagnosis, MRI was also the preferred modality to monitor the progression of disease and effect of treatment in our study. (FIGURE 4)
The global guidelines for the diagnoses and management of mucormycosis by the European Society for Clinical Microbiology and Infectious Diseases and European Confederation of Medical Mycology (13) was followed with certain modifications (FIGURE 5). Medical antifungal therapy with or without surgical debridement along with glycemic control or control of any other risk factor is the mainstay of management. (13) In addition, 1 ml of retrobulbar amphotericin B deoxycholate in the dose of 3.5mg/dl was injected for stages 3A-3B, on alternate days for 3 days followed by 1 day off before the next cycle. Quadrant was decided based on route of spread as determined on GdMRI. The most common side effects noted included chemosis (85%), pain (60%), and proptosis (15%). In the recent reports published on CAM, retrobulbar amphotericin was given in one patient in the recent study by Dave et al, (15) and they reported radiological resolution with uneventful follow up at 6 months of follow up. Although there is paucity of literature on the safety and efficacy profile of the treatment method, we found that retrobulbar Amphotericin injection, when indicated, caused radiological resolution in atleast 50% patients after 1 cycle of therapy and in 65% patients after 2 cycles. However, larger studies with a non covid control group is needed to prove the efficacy of the same. Overall, the treatment success rates of their study and the current study were 60% and 68.5%, respectively (p = 0.2).
Orbital exenteration is done in cases with no visual potential, with diffuse orbital involvement, but with the disease limited to the orbit without or minimal extension beyond cavernous sinus. (9) Few studies have even highlighted orbital exenteration in cases with CNS involvement to be detrimental to survival. In our study, orbital exenteration along with PNS debridement was done in 22.8 % patients. (FIGURE 5). With the mean follow up being at least 30 days, 100% of the patients with stage 4 ROCM who had undergone orbital exenteration survived and 87.5% showed regression of disease burden (P < 0.01). This was in comparison to 100% mortality seen in those who did not undergo exenteration. Thus, contrary to current belief, surgery in such patients may drastically improve survival, though larger studies are needed to prove the same. In patients with Stage 4 disease, we found that orbital exenteration was helpful in increasing survival besides disease reduction. Till date, results from our study indicate that mortality with CAM was 22.85 % and disease progression was seen in 10% of the cases; comparable to the overall mortality rate of 34% in the series by TV Dave et al. (15) (p= 0.48) These results are however likely to change over time while the patients are followed up for a longer duration.