The Co-infection of Mild COVID-19 and Rhinocerebral Mucormycosis in a Patient Without Diabetes or Prior Steroid Use

In a fast-evolving COVID-19 pandemic, co-infection with mucormycosis has been reported in some parts of the world. It is still unknown whether one of the either diseases makes the patient susceptible to developing the other. The co-occurrence of them significantly elevates the mortality risk and is commonly reported in immunocompromised individuals. We herein report a case of COVID-19 infection with rhinocerebral mucormycosis without prior steroid use or underlying immunosuppressive diseases.


Introduction
There are a few cases of COVID-19 infection and associated mucormycosis that are described around the world. But most of the co-infections are attributed to steroid use that is related to the COVID-19 infection or any underlying immunosuppressive conditions like diabetes mellitus [1].
However, some susceptible patients can develop them as co-infection without any identifiable risk factors. Therefore, the prime goal is to have high clinical suspicion and diagnose them as quickly as possible and manage them with the inputs from the multidisciplinary team appropriately.
There are several types of mucormycosis infection, namely the cutaneous, rhinocerebral, pulmonary, gastrointestinal and disseminated variants. The rhinocerebral variant that occurs nearly in half of the affected patients starts in the nose and eventually reaches the orbital cavity and central nervous system [2].
Aggressive treatment with intravenous antifungals needs to be started as soon as possible for a good outcome [2]. Due to the destructive nature of the disease, complete recovery sometimes needs repetitive surgical interventions.

Case Presentation
A 59-year-old South Asian female patient with no premorbid conditions (unremarkable past medical history) presented with fever, productive cough and right-sided periorbital swelling and complete drooping of the right eyelid with discoloration for the one-week duration ( Figure 1). Right-sided vision has become gradually obscured over the days. She denied any shortness of breath upon exertion or at night. She had no urinary symptoms and the bowel habit was unaltered.

FIGURE 1: The patient with the periorbital discoloration and complete ptosis
On examination, she was febrile, but not pale or icteric. There was no lymphadenopathy. Neck stiffness and Kernig's sign were not detected. She had no peripheral stigmata of infective endocarditis. There was no pitting ankle edema. Neurology examination showed right-sided complete ptosis with third nerve palsy without pupillary involvement. The right-sided visual acuity was 6/12 with a preserved left-sided vision. The other cranial nerves (except the second and third cranial nerves) and upper and lower limbs were neurologically unaffected.
Cardiovascular examination showed a blood pressure value of 130/85 mmHg with a heart rate of 96 beats per minute which was regular and of good volume. There was no murmur. Respiratory system examination revealed a respiratory rate of 22 per minute and oxygen saturation of 96% on room air. The modified exertional desaturation test was negative. Chest proper examination was unremarkable except for a few occasional coarse crepitations. The abdomen examination was virtually normal. The following investigations were performed ( Table 1).  The magnetic resonance imaging of the brain and sinuses was done to evaluate the extent of the involvement. It revealed right-sided orbital subperiosteal abscess formation ( Figure 2) with evidence of right-sided frontal, maxillary and ethmoidal sinusitis ( Figure 3).

FIGURE 2: Magnetic resonance imaging of the brain and paranasal sinuses showing right-sided periosteal abscess formation FIGURE 3: Magnetic resonance imaging of the sinuses showing rightsided frontal, maxillary and ethmoidal sinusitis
Ear, nose and throat team opted to perform the rigid nasal endoscopy from which residual sinus secretion was obtained. It was incubated on the Sheep blood agar at 37 degree celsius for 48 hours, which showed multiple colonies of filamentous fungal growth ( Figure 4).

FIGURE 4: Sheep blood agar (SBA) showing colonies of filamentous fungal growth
Microscopy of the growth under light microscope (40 x 10) revealed broad non-segmented hyphae suggestive of mucormycosis ( Figure 5). The culture was sent to the reference laboratory and was confirmed as mucormycosis species.

FIGURE 5: Microscopy of the growth under light microscope (40 x 10) showing broad non-segmented hyphae
She was admitted to the COVID-19 isolation unit. Her fasting blood sugar and the capillary blood sugar readings remained within normal range throughout. With the clinical suspicion, we started intravenous Liposomal Amphotericin 3 mg/kg/ day before the receival of the biopsy report. A multidisciplinary team meeting was arranged encompassing the consultant physician, consultant ear, nose and throat surgeon, consultant microbiologist and consultant surgeon to arrive at a comprehensive management plan. For the mild COVID-19, considering a secondary bacterial infection (as evidenced by the patchy inflammatory shadow on the chest x-ray), we started Intravenous Ceftriaxone 1 gram twice daily and oral Clarithromycin 500 mg twice daily with the multidisciplinary consensus.
The patient was well-hydrated and the renal function was monitored every other day considering the nephrotoxic nature of the antifungal therapy. On day 10, patient's COVID-19 polymerase chain reaction turned negative and the patient was taken out of the COVID-19 isolation unit. The antibiotic were omitted at the end of two weeks. After four weeks of intravenous Amphotericin, the fungal culture was repeated from the maxillary sinus which was negative for fungal hyphae. Patient's periorbital swelling improved and inflammatory markers returned to normal values. The patient underwent surgical debridement twice by the ear, nose and throat team during the admission to clear the residual tissue. She was discharged after one month of admission with a comprehensive follow-up plan.

Discussion
COVID-19 infection is categorized into mild, moderate and severe forms according to the severity of the illness. The common clinical presentations include fever, cough and shortness of breath. Supplemental oxygen and corticosteroids are the key aspects of the treatment protocol for COVID-19 [3]. COVID-19 patients with persistent hyperglycemia are in the risk zone of developing mucormycosis.
Although the main risk factors for the development of mucormycosis are touted to be excessive antibiotic use, irrational steroid use, diabetes and hypoxia, environmental factors may play a significant role in enhancing the disease progression [4].
This exciting manuscript has described that that is not always the case. Some instances of coexisting COVID-19 infection and mucormycosis have no underlying etiological basis.
Mucormycosis is an acute fungal infection caused by the members of mucoraceae family [5]. Rhizophus species are the most common causative agents in this group. It can occur as an opportunistic and fatal fungal disease in immunocompromised patients such as those with diabetes. The most common clinical form is the rhino-orbito-cerebral variant [5]. Before the development of the pulmonary and disseminated manifestations, mucormycosis commonly begins as the rhino cerebral form. Infection begins in the nasal cavities and paranasal sinuses and progresses to its full form. The common presentations are facial swelling, headache, fever, eyelid drooping and black lesions on the periorbital and nasal region. Infarction and necrosis of host tissues occur due to the invasion of non-septate hyphae. The diagnostic tests are mainly histopathology, direct testing, and culture of clinical specimens [5]. The treatment option is intravenous liposomal Amphotericin [5]. The therapy must continue until the patient makes a complete clinical and radiographic resolution [6].
In our patient with an unremarkable past medical history, we established a diagnosis of mild COVID-19 infection and rhinocebreal mucormycosis. With the high clinical suspicion, we started the intravenous antifungals early in the treatment and liaised with the ear, nose and throat team for the surgical debridement of the necrotic tissue. We followed a multidisciplinary team approach which was so efficient and the patient made a complete recovery after a course of four weeks. We stopped the antifungal therapy after one month as the patient made a convincing clinical and radiographic resolution.
Mucormycosis is a life-threatening disease and the association with COVID-19 incurs a worse prognosis. Though the glucocorticoid therapy can mount a response against the interleukin-6 mediated cytokine storm in COVID-19, its overuse has predisposed to the development of mucormycosis. Especially in South Asian countries such as India with a high population, steroid use is strongly associated with mucormycosis [7].
In literature, it is the first reported case of mucormycosis and COVID-19 without steroid use or diabetes in the world. In nondiabetic individuals, several case reports describe that steroid use and immune dysregulatory mechanisms in COVID-19 are the main contributory factors for the co-infection and most of such cases are reported in the South East Asia [8]. Some case reports from India suggest that steroid usage during COVID-19 transiently causes hyperglycemia due to which the already immunocompetent individuals get the co-infections [9].
Some case reports accounting the aforementioned co-infection in the immunocompetent individuals suggest severe COVID-19-induced lymphopenia, T-cell dysregulation and other cytokine dysregulation as the probable causes for such a rare association [10].
There are several proposed reasons behind the development of co-infection in an immunocompetent individual. The repeated steaming during the COVID-19 era suppresses the nasal tract's advantageous microbiome and nasopharynx associated lymphoid barrier thereby favoring the entry of the fungus via the nasal route [11]. Dysbiosis of gut microflora has been caused by the abundant use of zinc supplementation during the COVID-19 times, providing a favorable environment for fungal growth [11]. Via the gut-lung axis, mucorale specific T cells (the CD4+ and CD8+ cells) interact with the gut microflora, which determines the overall functionality of the immune system, it's therefore important to maintain the gut microbiome intact. In addition, excessive vitamin A supplementation to get rid of COVID-19 may impair the humoral immunity (antibody-mediated) which in turn enables the fungal growth in our body [11].
The association is mostly observed during the hot and summer seasons with lower relative humidity in the tropical areas, raising the possibility of a seasonal trend [11]. However, the scientific data is lacking on this regard. More studies need to be done to evaluate the seasonal variation, ambient temperature and humidity and its relationship with the co-infection. The oxygen therapy during COVID-19 seems to have no impact on the development of mucormycosis [11]. Malnutrition related to COVID-19 may, nonetheless, play a role in the fungal invasion.
As there was a surge in the mucormycocis cases during the second COVID-19 wave especially in India, it was speculated that due to the shortage of oxygen supply systems, patients developed silent hypoxia (happy hypoxia). And thus, they experienced prolonged low oxygen levels ( <95%) and the hypoxia favored the virulence of the pathogenic fungi like mucormycosis [12]. Hypoxia is postulated to affect the transcriptional levels of genes associated with fungal virulence. Similarly, hypoxia induces the endocytosis of some mucorale species and shifts the source of fungal energy metabolism from carbohydrate to fatty acids, thereby using up lipid from the host serum [12]. This explains why the destructive lesions are more concentrated in the face area where the sebaceous glands are abundant. Furthermore, hypoxia inducible factor (HIF) causes tissue damage and immune malfunction [12].
In diabetic patients with COVID-19, strict glycemic control and careful steroid use is key to the prevention of mucormycosis [13]. And, it must be remembered that in non-diabetic patients with COVID-19, rational use of steroids is recommended to minimize the risk of mucormyscosis.
Treating mucormycosis is a multidisciplinary team approach which requires a set of radical and repetitive surgical debridement along with intravenous antifungals [14].