A new study conducted in India identifies the role of high blood sugar levels in predisposing patients to mucormycosis infection. The study, which is available on the preprint server medRxiv*, also provides guidance on how to mitigate the risk of this fungal infection.
What is mucormycosis?
Mucormycosis is a sporadic fungal disease caused by angio-invasive fungi of the order Mucorales and almost exclusively occurs opportunistically in immunocompromised patients.
This disease swiftly causes rhino-orbital-cerebral tissue destruction and death that often extends to the lungs, skin, digestive tract, or even systemic circulation.
The incidence of mucormycosis has recently surged to more than double its normal rate because of its prevalence among patients with coronavirus disease 2019 (COVID-19) in India.
This suggests that COVID-19 is a risk factor for mucormycosis, either as a result of the weakened immune system or an indirect result of the therapies; such as corticosteroids, that have been used in the management of COVID-19.
Not only is mucormycosis itself life-threatening, but the high cost of treatment mandates that rigorous efforts be made to prevent it.
India has had high rates of mucormycosis, even before the COVID-19 pandemic, that are about 70 times the global prevalence.
This increased incidence of mucormycosis could be because of the high humidity and ambient temperatures in this nation; as well as the prevalence of diabetes.
Rural areas in India have often been particularly vulnerable to mucormycosis.
Previous studies indicate that males, typically in their forties and fifties; are more likely to be affected than females by mucormycosis.
Recently, the onset of mucormycosis has occurred about 3 weeks after the beginning of COVID-19 symptoms; with the nose and orbital cavities typically affected first.
Most of the COVID-19 patients with mucormycosis have reported poor control of their blood sugar; were on systemic corticosteroid therapy or had diabetes.
These factors were absent in only one patient in the current study, differing from earlier reports where a minority of cases; up to 33% in some reports, lacked any of these risk factors.
Interaction of risk factors
Fungal sporangiospores and hyphae are typically destroyed by the neutrophils and macrophages of the innate immune system.
The activity of these immune cells subsequently triggers an adaptive immune response; which is highlighted by Th-17 cell activation and stronger neutrophil activity.
Within the nasopharynx, neutrophils are prematurely activated with relatively low numbers of T-, B- and natural killer (NK) lymphocytes.
This abnormal pattern is clearly observable during week 2 of the COVID-19 infection; perhaps accounting for the peak in mucormycosis cases during this period following COVID-19 onset.
In addition, the invasive nature of the fungi may be exacerbated by the endothelial cell abnormalities and vascular injury associated with this viral infection.
Hyperglycemia is an inhibitor of neutrophil activity and chemotaxis, macrophage phagocytosis, and NK cell degranulation.
This condition also upregulates glucose-regulated protein (GRP78) expression on the surfaces of cells; which is an invasion factor for Mucorales.
The highest risk of mucormycosis has been among individuals with blood glucose exceeding 400 mg/dL.
The prolonged use of corticosteroids also increases the risk of mucormycosis, as these drugs suppress macrophage and neutrophil activity and promote hyperglycemia.
Thus, postprandial blood sugar measurement is essential for glucose control during steroid therapy, unless it is used short-term; especially in those with higher HbA1C levels before the commencement of therapy.
Mucormycosis associated with COVID-19 is almost eight times more common among patients on steroid therapy.
This should not prevent the appropriate use of steroids in severe COVID-19; where they have been shown to save lives; however, it should serve as a warning against their use in mild cases of COVID-19.
Zinc is an essential micronutrient that is safe and inexpensive as a supplement.
It is key to the proper functioning of the immune system, reduces pro-inflammatory cytokine secretion; prevents undue lymphocytopenia, and mitigates airway inflammation in COVID-19.
The use of zinc has been linked to reduced mucormycosis risk among COVID-19 patients.
The severity of COVID-19 vs mucormycosis risk
While over one in three COVID-19 patients with mucormycosis had a history of severe COVID-19 in the current study; previous studies have reported severe COVID-19 in up to 75% of patients with coronavirus disease-associated mucormycosis (CAM).
This discordance will need to be further investigated by prospective studies in order to eliminate survivorship and selection biases.
However, ferritin levels are high in severe COVID-19, including in mucormycosis cases.
This is a significant observation, as the Rhizopus species depend on iron for their pathogenesis and growth.
Other risk factors
The use of both surgical and/or cloth masks for extended periods have been linked with higher mucormycosis incidence, as Rhizopus tolerates high temperatures and moisture.
Risk of Coronavirus disease-associated mucormycosis depends on the type of mask as well as duration of usage. * represents significant difference compared to use of N95 mask for <2 hours.
Mask use for one hour raises the skin temperature around the mouth, while respiratory tract infections are more common with cloth mask use as compared to no masks or other types of masks. This risk could be related to ineffective cleaning of masks, inappropriate reuse of masks, or simply because they hold moisture.
On the other hand, mask use may be a proxy for increased exposure to spore-containing dust or soil.
These preliminary findings need to be further explored.
Repeated nasopharyngeal swab testing has been linked to a higher risk of mucormycosis; which may be analogous to the skin mucormycosis seen at sites of local trauma. Steam inhalation showed no such association.
What are the implications?
This is the first sizable study comparing cases and controls to identify risk factors for COVID-19-associated mucormycosis.
Notably, the controls in this study were taken from a single center; which may have influenced the results, as cases are often treated with different protocols at different centers.
The retrospective nature of the study may have also influenced the findings due to missing data.
Overall, the authors found that CAM is strongly associated with diabetes; poor glycemic control, and systemic steroid use. The need for oxygen supplementation or hospitalization for COVID-19 was not found to increase the risk.
Cloth mask use for prolonged periods and repeated nasopharyngeal swab testing were both found to be risk factors for the fungal infection in this study for the first time.
In contrast, N95 masks were protective against CAM.
If confirmed by further research, appropriate modifying recommendations should be issued to reduce the incidence of this potentially deadly complication of COVID-19.