Correlation Between the New Delta Variant B.1.617.2 of COVID-19 Virus and Mucormycosis – An Invasive Fungal Infection

Introduction

The recent Delta virus B.1.617.2 of 2021 (considered second wave) in India has left thousands in a state of panic, stress and fear. Negligence, lack of awareness and precautions were the reasons behind the increase in number of COVID-19 cases, and the new emerging variants also contributed to the havoc. 

The COVID-19 infection is caused by severe acute respiratory coronovirus 2 (SARS-CoV-2) and is associated with a range of disease patterns, from mild to life threatening pneumonia.¹ Till June 2021, the COVID-19 has stretched to over 215 countries and caused nearly 177,108,894 confirmed cases and 3,840,223 deaths globally [WHO- 19/06/2021]. SARSCoV-2 causes Acute Respiratory Distress Syndromes (ARDS) like SARS-CoV1 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV).^2,3 Apart from diffuse alveolar infection and severe inflammatory exudation, COVID-19 positive patients also have immunosuppression with a decrease in CD4+T and CD8+T cells and increased levels of IL-2R, IL-6, IL10, TNF-alpha and other inflammatory markers.^4,5 COVID-19 positive patients admitted in ICU who are intubated/mechanical ventilated and with underlying conditions such as respiratory disorders, cytokine storm or on steroid therapy are at risk of developing mucormycosis.

We report eleven patients who were under homeisolation for COVID-19 infections, who during the course developed rhino-maxillary mucormycosis.

Case Presentations Eleven patients were referred from a Primary Health Centre to maAx Super-Speciality Hospital, Shimoga, India. On examination, four patients showed diffuse soft tissue enlargement in the preseptal, pre-maxillary and malar regions. Three patients complained of mobile maxillary teeth and four patients with nasal blockages and exposure of black bare bone with incomplete mucoperiosteum over the hard palate with fistula causing oro-nasal communications. These eleven patients were aged between 41 to 50 years and were non-diabetic, but with a history of recovery from COVID-19 infections. All the eleven patients confirmed being positive for reverse-transcriptase polymerase chain reaction test (RT-PCR) done for SARS-CoV-2. History also revealed that they were under home-isolation and were under medication (Tablet Dolo 650, three to four times a day). A nasal biopsy reported broad aseptate filamentous fungal hyphae suggestive of mucormycosis, which was confirmed on culture. All the eleven patients underwent MRI scanning (Figure 1), which demonstrated thickening of mucosal layer of the maxillary sinuses along with bony erosions.

Three out of eleven patients refused further investigations and complained of psychological and mental stress due to COVID-19 and hence refused treatment for mucormycosis. Despite the explanation of possible complications of mucormycosis, these patients refused treatment. Eight out of 11 patients underwent surgical debridement (Figure 2) followed by injection Amphoterecin B (liposome) 5 mg/kg/body weight diluted in 5% Dextrose for 10 days and tablet Posacanazole 300 mg once daily for 15 days. All the eight patients were comfortable and satisfied two months post the surgery and are on regular follow-up once in 15 days. All the eleven patients in this article were similar as compared to other cases reported in literature in terms of demographics, medical history and clinical features. Looking at the pattern of the virus, questions arose regarding the mutated variant of COVID-19, B.1.617.2 causing mucormycosis. All of us have to be prepared and stay cautious of the risk of secondary invasive fungal infections (mucormycosis) in patients with positive COVID-19 infection (either hospitalized or home-isolated patients).

Discussion

The Delta variant or B.1.617.2 of COVID-19 infections, refers to the merging of two mutated virus strains that go on to form a third, super infectious strain. The B.1.617.2 Delta variant contains two separate mutated virus variants, namely E484Q and L452R. With the help of genome sequencing and sample testing, the first case of double mutation in India was found in Maharashtra state. Earlier lab results reported a sharp rise in the E484Q and L452R mutations since December 2020. Given that the Delta variant carries the genetic code from two other mutations, it becomes easier for it to rip into the human immune system and invade into the organs. As the new variants tend to modify the structure of the spike protein, it is well-organized in attaching itself to the human host cells and multiples, doing more damage than the initial COVID strain (World Health Organisation-2021). The US Centers for Disease Control and Prevention has classified Variants of Concern into B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.427 (Epsilon), B.1.429 (Epsilon) and B.1.617.2 (Delta). The World Health Organization classified Delta as Variant of Interest. 

Necrosis of highly vascular maxillary bone is very rare. But the occurrence of necrosis increases due to metabolic disorders, trauma and infections. Mucormycosis of maxillary bone is a common fungal infection in diabetic and immuno-compromised patients, but can affect healthy individuals too.⁷ The predisposing factors for this fungal infection are uncontrolled diabetes (patients with ketoacidosis), malignancies (lymphoma and leukemia), renal failure, organ transplants cases, long term corticosteroids and immunosuppressive therapy, burns, cirrhosis, protein energy malnutrition and AIDS.^7,8,9,10 

Mucormycosis is an opportunistic disease caused by a group of saprophytic fungi, belonging to the order Mucorales and class Zygomycetes.^11,12 The spores of these organisms are dispersed into the air from decaying material, and the mode of spread of infection is via inhalation route and the infection first starts in the nose and paranasal sinuses.^8,11,13 The fungal infection has a propensity for vascular invasion, forming thrombi inside the blood vessels, leading to diminished blood distribution and tissue necrosis. Iron plays a very important role in the growth of Invasive Fungal Infections (IFI). Fungal hypae produce ‘rhizoferrin’, which binds with iron. Rhizoferrin is then accepted by the fungus and becomes accessible for its vital essential functions. Patients with diabetic ketoacidosis are at elevated risk of developing IFI due to elevation in the serum iron.^11,17

Mucormycosis has various clinical presentations or forms based on systemic involvement namely, rhinocerebral (noticed in uncontrolled diabetic patients), pulmonary (noticed in patients with leukemia and patients receiving chemotherapy), gastrointestinal (noticed in extremely malnourished children), cutaneous (noticed in burns patients) and disseminated forms (noticed in patients with pulmonary mucormycosis).^14,15,16,18 

There are limited number of publications on positive COVID-19 patients with invasive mycoses. In China, Chen et al. worked on fungal culture and found five cases of fungal infection, including one case of Aspergillus flavus, one case of Candida glabrata and three cases of Candida albicans. ¹⁹ A German study revealed COVID-19 associated invasive pulmonary aspergillosis (IPA) found in five of 19 critically ill patients with moderate to severe ARDS.20 In Netherlands, six patients presumed of IFI in 31 ICU patients, of which five were identified as Aspergillosis fumigatus. ²¹ Among the first five well-mentioned French COVID-19 patients, an old severely ill man was co-infected with Aspergillosis flavus by tracheal aspirate culture.²²

Studies have shown that SARS-CoV-1 and SARSCoV-2 belonged to the same species and have similar prevalence, biological and clinical characteristics.²³ A research found IPA diagnosed in 83 (19%) of 432 patients admitted with influenza (higher in immunocompromised patients), and in the event of IPA, the mortality increased from 28% to 51%.²⁴

Doctors and clinicians should concentrate on patients with fungal infections, especially in asymptomatic, severely ill and immuno-compromised cases. Hence, it is essential for these patients to receive fungal pathogens surveillance, including

(i) Clinical evaluation –direct microscopy and culture

(ii) Serology test - antigen and antibody

(iii) Histopathology

(iv) PCR-based methods - Real time polymerase chain reaction technique and molecular detection can be performed to detect pathogens²⁵

Hospitalized COVID-19 patients share risk for invasive fungal infections, particularly in chronic respiratory disease cases, patients on corticosteroid therapy, intubated patients or on mechanical ventilation, cytokinic storm etc.⁶ Invasive mycoses is usually suspected based on results of direct microscopy or fluorescent brighteners from clinical specimen such as sputum, bronchalveolar lavage fluid (BALF) and skin lesions showing mucorales hyphae which are non-septate or pauci-septate.²

Since 2019, the treatment for mucormycosis is complete surgical resection at the earliest as suggested by European Confederation of Medical Mycology (ECMM) and Mycoses Study Group Education and Research Consortium. In neutropenic patients, (those with graft-versus-host disease or high risk factor) primary prophylaxis with Posaconazole may be recommended.² Amphotericin B lipid complex, liposomal Amphotericin B and Posaconazole oral suspension are the recommended drugs of choice.

Conclusion

Maxilla forms the upper jaw and is the primary bone of the face holding the upper teeth. It plays a key function in mastication and speech. Necrosis of maxilla can be due to bacterial and fungal infections, and the proximity of the maxilla to nasal mucosa and maxillary sinus may also contribute to it. COVID-19 disease is associated with significant incidence of fungal and bacterial infections due to immune dysregulation. Longterm use of steroids, broad spectrum antibiotics (part of treatment for COVID-19) may direct to the development of fungal diseases. By analyzing the retrospective study of SARS worldwide, we can conclude that fungal infections associated with COVID-19 may be missed or misdiagnosed. We were surprised to see eleven non-diabetic patients with mucormycosis who were under home-isolation for suspected Delta variant of COVID-19. As a life threatening infectious disease, these patients showed elevated inflammatory cytokines, and impaired cell mediated immune response with reduced CD4+T and CD8+t cell counts, indicating its propensity to fungal co-infections. Physicians should be alert of the possibility of IFI in patients with COVID-19 infection.  

As physicians and surgeons, our collective goals should be:

(i) Gather original epidemiological data regarding fungal infections in patients with COVID-19 (during ICU stay, with long term corticosteroids and patients under homeisolation).

(ii) Follow prompt early diagnosis and treatment with subsequent reduction of mortality and morbidity.

(iii) The use of therapeutic agents should be monitored to achieve a therapeutic effect at the lowest dose and shortest duration.

(iv) Over usage of steroids/monoclonal antibodies/ broad-spectrum antibiotics may lead to the development IFI in COVID-19 patients.

(V) The Delta variant B.1.617.2 of COVID-19 infection is a Variant of Concern and Interest.

But, the question still arises – Can the Delta Variant B.1.617.2 cause Invasive Fungal and Bacterial Infections in non-diabetic, home-isolated COVID-19 patients?? As physicians and surgeons, more emphasis must be given to this Variant of Interest and Concern.