Here, we performed a retrospective study to assess the patients with an active or documented history of COVID-19. In total, we reported 52 patients with CAM with symptomatic active/history of COVID-19 and compared them to 130 randomly selected patients with COVID-19, but not CAM. Based on our analysis, although the mean age of the CAM group was higher than the control group, we did not find any significant association between the age and the risk of CAM. Meanwhile, the mean age in our study (57-year-old) was similar to the reported number in the recent meta-analysis (22) (54.6-year-old), which was composed of 17 studies (101 patients). This might be because of the higher age of regular COVID-19 in the study period of time in our center. The mean age of COVID-19 patients varies in a wide range, while in a study with more than 7 thousand of COVID-19 patients in Iran, the mean age of infection was reported 41.48 ± 16.35 (23). According to the same meta-analysis (22), the male gender is commonly affected by CAM; we observed a higher number of males than controls (63.5% vs. 53.1), but not in a statistically significant manner in comparison to the regular included COVID-19 patients. This might be because of a different pattern in Iran since the other study from Iran has reported 66% as the percentage of affected men in the reported group with CAM (24). Although in the literature, the mean interval between CAM clinical manifestation and the time of COVID-19 diagnosis has been reported in the range of 15–24 days, (mean of 20 days), we found this interval in a wider range, 0–51 days, but with similar mean, 16.63 ± 8.4 days. This period of time could be longer for some cases since confirmation usually happened 2–3 days after the initial signs/symptoms. In our study, we detected more severe COVID-19 among those in the CAM group in comparison to regular COVID-19. Although choosing control patients from COVID-19 patients who survived the diseases might affect the results, approximately half of the patients in the CAM group were categorized in the severe group.
Considering the fact that the number of reported CAM have has increased since the emergence of Delta-variation, some studies have suggested that the association might be because of the dominance of the last variation of concern, the Delta variation (15). We considered this speculation in our analysis, based on an estimated time period of variations dominancy, but not genotyping of viruses. Although it might not be fully trustable, it could be speculated that variations might not be involved, but with increasing in the cases of patients, and allocating attention to the CAM more cases are being reported. However, studies on the confirmed variations of viruses might be helpful to clarify.
It has been shown that DM is a possible risk factor for the development of CAM (16), which is in line with our results. 29 of 52 (55.8%) patients in the CAM group had a known history of DM, which was observed in 19 (14.6%) in the control group. However, new-onset post-COVID-19-related hyperglycemia was detected 46.2% in the CAM group, and 63.8% in the control patients. It has been speculated that COVID-19 could lead to hyperglycemia, although the exact underlying mechanism remained unknown (25). Patients will remain hyperglycemic in the absence of proper treatment and close monitoring, which could easily happen during the collapse of the healthcare system due to pandemics. A higher percentage of post-COVID-19 hyperglycemia in patients with CAM could be explained by close monitoring of patients in the CAM group in comparison to the regular COVI-19 patients. In our cases, hyperglycemia was probably controlled better in the CAM group as they were hospitalized and were monitored in a daily manner. In our study, not only DM in individuals but also a familial history of DM was associated with CAM development. This only shows the higher risk of DM in individuals who have familial history of DM as well, as was shown in previous studies (26). Thus, we need to have close monitoring of such patients. The history of corticosteroid therapy was also another mentioned risk factor for CAM development in COVID-19 patients. In our study, we found that 5 patients in the CAM group, but no one in the control, have received high dose pulse therapy of corticosteroids. This suggests a high-dose corticosteroid as a possible risk fact. However, since most of our patients had a history of treatment with low-dose corticosteroid (i.e., dexamethasone), we did not find any significant association. Moreover, we found smoking might be a risk factor for development, which is in line with the fact that smoking can increase the risk of invasive fungal infections (27). In addition to the risk factors, we found some serological markers, such as creatinine and liver enzymes that are associated with CAM. Since these factors were evaluated after CAM development and might be affected with disease and treatments, we only can consider them as factors associated with CAM, but not risk factors.
In this study, we have noticed that the percentage of CAM among the patients with mucormycosis unrelated to COVID-19 was 55.3%. This suggests that the development of mucormycosis is more frequent among the patients with active and resolved COVID-19 patients. In the meantime, the number of real patients with CAM might have been underestimated, since some COVID-19 patients might have missed identifying due to the asymptomatic nature of the disease in some patients. More precisely, they might have experienced asymptomatic COVID-19, while due to lack of symptoms, they were not evaluated for the COVID-19 test.
We have selected the control group, COVID-19 patients, from the patients who had at least follow-up to make sure that the possible risk factors are more trustable. Random selection of COVID-19 patients has been done in only surviving patients, because one of our goals was to identify risk factors for the development of CAM, and we needed to have at least three months of follow-up of patients to make sure that CAM has not happened. Thus, we were unable to compare the mortality rate between COVID-19 alone and CAM; according to the literature, the mortality for COVID-19 in Iran is ~ 5% (23). Additionally, only inclusion of surviving patients might affect the accuracy of some reported markers which are associated with CAM development, since some of these factors might be associated with mortality. In order to evaluate this, we excluded the expired patients in the CAM group and repeated the analysis. We found that none of the variables, except hyperglycemia (became statistically insignificant) and lymphocyte number (became significant) had been changed. It is worthy to note that because the number of patients who were evaluated for Interleukin-6 (IL-6) was less than the acceptable number for statistical analysis, then in this regard we could not differentiate between the two groups.
In conclusion, it is obvious that patients with either active or resolved COVID-19, especially smokers with a history of DM are at a higher risk of mucormycosis development. Those with risk factors should be closely monitored within the few months after recovering from COVID-19. CAM looks to be more fatal in older patients with more severe COVID-19. However, proper antifungal treatment along with doing surgery during its golden time could significantly decrease the mortality of CAM.