Incidence of Mucormycosis in a Tertiary Care Hospital During Covid First Wave-A Retrospective Study

Abstract

Rhino orbital cerebral mucormycosis is a medical emergency; though rare it’s a life threatening infection in patients. It commonly occurs in immunocompromised patients due to various causes. A retrospective study was conducted in tertiary care centre wherein 30 non-covid, diabetic patients were treated for mucormycosis. All underwent intensive debridement and diabetic management along with antifungal- amphotericin. All the cases improved with aggressive therapy: medical and surgical. Early recognition and treatment is needed to prevent morbidity and mortality.

Introduction

Mucormycosis is an uncommon fungal infection which has the ability to invade the blood vessels and can cause fulminant necrotizing infection when the immunity of the host is compromised, most commonly diabetes mellitus. Although mucormycosis is a systemic disease, the most common and most aggressive is rhino-orbital cerebral form of presentation.

Mucormycosis

ROCM (Rhino-Orbito-Cerebral Mucormycosis) is an uncommon, acute, aggressive fungal infection occurring in several immuno-compromised states including diabetes which is the most common (60–81%) predisposing factor. Diabetes predisposes to infection as seen in majority of cases of ROCM in different series [1–3].

History: In 1815, Meyer recognized the pathogenicity of mucor organisms. In 1943, Greogory et al., showed the predilection of phycomycotic infection in diabetic patients and provided the description of pathologies which later became a clinical triad of diabetes mellitus, orbital cellulitis and meningo -cerebritis. The term mucormycosis was proposed by Baker. These infections are aggressive, granulomatous, and acutely infective and opportunistic infection that is caused members of phycomycetes class of fungi, which belong to subphylum Mucormycotina. A higher level of phylogenetic classification of fungi has also been reported by Hibbett et al. [4–8]

Taxonomy: Zygomycosis was used to describe invasive fungal infections caused by zygomycetes, which are irregularly branched pauci septate or aseptate molds that reproduce sexually via formation of zygospores. Subsequently a reclassification followed dividing the Zygomycetes into two orders, namely Mucorales and Entomopthorales [9].

Microbiology: There are several genera of phycomycetes, but the genera that are most commonly implicated in causing mucormycosis are Rhizopus, Mucor, Absidia. Rhizopus is responsible for 70% of reported cases of rhino-orbital cerebral mucormycosis. Mucormycosis is an ubiquitous organism and frequently air borne and can be found in bread mold, soil, manure and decaying vegetation [10].

Epidemiology: The disease as predilection for distinct population namely with diabetic keto acidosis, immunocompromised states, severe neutropenia, hematopoietic malignancies, chronic steroid therapy Figs. 1, 2, 3.

Fig. 1.

Pre and post operative clinical picture

Fig. 2.

Resected specimen

Fig. 3.

ENT surgical procedures

Pathophysiology: Hyperglycemic state impairs phagocytosis and this favors rapid growth of Rhizopus. Successful survival of the fungus in acidotic environment due to diabetic keto-acidosis is favored by ketone reductase system in Rhizopus. Dissociation of iron sequestering proteins in the serum caused by acidosis promotes virulence and survival. The acidic environment reduces the binding of iron to transferrin, there by more free iron and lack of dialysate inhibitory factor in patients with diabetes mellitus offer favorable condition for fungal multiplication. The hyperglycemia favors fungal growth by hyperglycation of iron sequestering proteins with impaired iron sequestration, enhanced expression of GRP78, a mammalian protein receptor, which increases binding of Mucorales and finally decreased phagocytosis associated with a high blood sugar state. Mucor is an angiotropic fungus having high tendency to damage the internal elastic lamina of blood vessels, dissecting it causes extensive endothelial damage leading to thrombosis and ischemia leading to gangrene eventually black necrotic eschar tissue formation. Mucormycosis is a systemic disease and it affects lungs, kidneys, musculoskeletal system, urinary bladder, gastrointestinal tract, heart and brain. Amongst these, ROCM is the most common. Isolated presentation of mucor have also been reported in middle ear, parotid, mediastinum, heart valves, uterus, urinary bladder and lymph nodes [11–13].

Clinical features

1. Nasal stuffiness

2. Blood stained nasal discharge

3. Foul smelling nasal discharge

4. Periorbital edema

5. Facial discoloration

6. Headache

7. Facial pain

8. Loosening of tooth

9. Facial paresthesia/Anesthesia

10. Sudden ptosis

11. Sudden loss of vision

12. Restricted ocular movements/Double vision

13. Unexplained fever

14. Focal seizures/Altered sensorium

Staging system for ROCM propose by Santosh G Honavar [14].

Biopsy: Direct histologic examination of scrapings and biopsies of involved tissue or paranasal sinus secretions are diagnostic. The fungal infection may be patchy, so repeated multiple biopsies may be required for definitive diagnosis. Histopathological examination with special stains such as Grocott-Gomori methanamine-silver nitrate, periodic acid-Schiff, calcofluor white demonstrate pathognomonic broad,irregular,non septate and right angled branching hyphae. Evidence of angio-invasion and tissue infarction were observed [15, 16]

Imaging: The radiographic findings in CT are rim of soft tissue thickening along the paranasal sinuses and bone destruction. These findings are non-specific, and it may be difficult to distinguish this aggressive form from other sino-orbital conditions. Rhino cerebral mucormycosis should be a strong consideration when there is lack of enhancement of mucosa, given its angio- invasive nature, because the hyphae likely invade smaller vessels Table 1. CECT showing the lack of enhancement in cavernous sinus is consistent with thrombosis of invasive fungus. Once the diagnosis is made, CT and MRI can help to delineate the extent of infection and can guide surgical debridement [17, 18].

Table 1.

ROCM staging

Stage	Involvement
Stage 1	Involvement of nasal mucosa 1a: Limited to the middle turbinate 1b: Involvement of inferior turbinate or ostium of the nasolacrimal duct 1c: Involvement of nasal septum 1d: Bilateral nasal mucosal involvement
Stage 2	Involvement of paranasal sinuses 2a: One sinus 2b: Two ipsilateral sinuses 2c: > Two ipsilateral sinuses and/or palate or oral cavity 2d: Bilateral paranasal sinus involvement or involvement of the zygoma or mandible
Stage 3	Involvement of Orbit 3a: Nasolacrimal duct, medial orbit, vision unaffected 3b: Diffuse orbital involvement (> 1 quadrant or > 2 structures), vision unaffected 3c. Central retinal artery or ophthalmic artery occlusion or superior ophthalmic vein thrombosis, involvement of the superior orbital fissure, inferior orbital fissure, orbital apex, loss of vision 3d: Bilateral orbital involvement
Stage 4	Involvement of CNS 4a: Focal or partial cavernous sinus involvement and/or involvement of the cribriform plate. 4b: Diffuse cavernous sinus involvement and/or cavernous sinus thrombosis 4c: Involvement beyond the cavernous sinus, involvement of skull base, internal carotid artery occlusion, brain infarction. 4d. Multifocal or diffuse CNS disease

Treatment: Its divided into.

• (i)Prevention of disease
• (ii)Early prompt diagnosis
• (iii)Reversal of immunocompromised status
• (iv)Appropriate aggressive surgical debridement
• (v)Rapid antifungal therapy
• (vi)Rapid antifungal therapy

Systemic liposomal/lipid complex amphotericin-B was given in all patients after confirmation with KOH mount and histopathological examination. Surgical debridement with ESS, subtotal maxillectomy, palatectomy, orbital exenteration are being carried out depending upon the extent of the disease. Amphotericin B is the gold standard in the systemic treatment of mucormycosis. Before the use of amphotericin B, the survival rate of mucormycosis was just 6% whereas after the introduction of amphotericin B this rate is dramatically increased to 60%. Another drug that can be used in systemic treatment is posaconazole. Oral Posaconazole can be chosen as a maintenance therapy after the completion of amphotericin B treatment. In addition to surgery and systemic therapy, local amphotericin B douching stopped the progression of the disease [19–22].

Prognosis: The survival rate depends on the number of sinuses that have been infected and extent to which they are infected. Mortality tends to be higher among older patients but survival rates are as high as 85% has been reported. Recent reports have suggested that the overall mortality rate following widespread use of amphotericin B in conjunction with surgical debridement has fallen to 40%. Impaired delivery of antifungals to the site of infection due to vascular thrombosis and; limited aggressive therapy because of the complex anatomy of the rhino orbital region cautions for early diagnosis and aggressive management in these patients [23–25].

Factors associated with poor prognosis in rhino orbital cerebral mucormycosis include.

• (i)Delay in diagnosis and treatment
• (ii)Hemiparesis
• (iii)Bilateral sinus involvement
• (iv)Facial necrosis

Materials and Methods

Study design: Observational retrospective study.

Place of study: Upgraded Institute of Otorhinolaryngology, Madras Medical College, Chennai during April 2020 to March 2021.

Sample size: 30.

Inclusion Criteria

• (i)Age > 20 years to < 72 years, (20 & 72 included)
• (ii)Patients with ROCM
• (iii)Diabetes mellitus

Exclusion Criteria

• (i)Patients with Chronic Kidney disease
• (ii)Patients with covid – RTPCR positive report

Pre Op Evaluation: Complete blood count, renal function test, Ultrasonogram Abdomen, Blood sugar Fasting and Post prandial, HbA1C.

Post Op Evaluation: Periodic diagnostic nasal endoscopy and suction clearance, Nasal douching.

Analysis

All Patients were Diabetic and All were Covid Negative

Among the 30 patients studied, 20 were male and 10 were female. 21 patients had nasal discharge, 8 patients had swelling of face and one patient had swelling of eyes as initial presenting symptom. The age distribution was 3 patients in 21–30 years age group;3 in 31–40 years age group;11 patients in 41–50 years age group; 9 patients in 51–60 years age group; 3 patients in 61–70 years age group and 1 patient who was 72 years old. The incidence was thus seen more common in patients in the fourth decade and least in seventh decade. Among the patients studied, ten patients had eschar in the hard palate and twenty did not have. In the group of patients studied, twenty patients had no visual complaints and ten patients had no perception of light. Involvement of facial skin was seen in 7 patients. Cavernous sinus involvement in the form of thrombosis was seen in 5 patients. Orbital procedure- exenteration; was done in 5 patients who had loss of vision due to the invasive fungal infection. It was done as a second sitting procedure.

As a part of surgical intervention, Endoscopic Sinus Surgery (ESS) was done in twenty seven patients; infrastructure maxillectomy was done in two patients and subtotal maxillectomy for one patient. Extent of maxillectomy differed as there was erosion of the maxilla due to the disease itself.

Discussion

A.Blitzer et al. study which did an analysis of 170 cases of paranasal sinus mucormycosis collected from the literature and 9 cases from their centre and revealed a 50% mortality for this disease. When analyzed according to decade, survival has increased to 70% in the cases reported from 1970–1979. There were no significant differences between the survivors and the fatalities when evaluated according to age, sex, laterality, or radiographic findings. There was a markedly poorer prognosis for those patients with hemiplegia, facial necrosis, and nasal deformity. The underlying disease was an important determinant of survival: 75% of patients with no systemic disease, 60% of diabetics, and 20% of patients with other disorders survived. Surgical debridement or radical resection and the use of amphotericin B significantly increased survival. Their combination further enhanced survival, especially in the diabetic [23].

In Kirdack et al. study male patient were 18 (50%) cases and female were 12 (40%). Most common predisposing factor was diabetes mellitus in 24 (80%) cases and other factors were tuberculosis 4 (13.33) and chronic renal failure 5 (16.66).Most commonly presented age group was 4th decade to 5th decade 11 (36.66) and 8 (26.66%) respectively. Most common symptom was nasal obstruction and sign was maxillary swelling 21 (70%). Most common radiological finding was cloudiness of sinuses 27 (90%) least common finding was intracranial extension 6 (20%). Most common used treatment modalities was amphotericin B24 (80%) and least used was surgical debridement by FESS 16 (53%). In their conclusion they stated that—in the management of mucormycosis and its different pathological forms- most aggressive form like rhino cerebral mucormycosis- prompt diagnosis based on clinical examination, reversal of predisposing condition and aggressive surgical debridement along with medical treatment remain corner stone of the therapy for this deadly disease [26].

In Carlos Zamora study, an early diagnosis and treatment is the key element to better survival rate in mucormycosis. Surgical debridement and antifungal drugs remain the mainstay of therapy. It is important to stabilize the patient if there are comorbidities (ketoacidosis, immunosuppression, etc.). Better methods of diagnosis have to be developed in regards to cost and time efficiency for a more guided early treatment. The answer is in new molecular methods which certainly elevate the total cost of treatment and it being still a challenge in world access [27].

In Aguilar et al. study, which included seven patients, three female and four male subjects; the mean age was 53.14 years. Four patients were immunosuppressed and three immunocompetent. Among the immunosuppressed patients three had diabetes and one had dermatomyositis. The symptoms were nonspecific: facial pain/headache, mucoid discharge and cacosmia. Maxillary sinus involvement was present in all patients. Two immunosuppressed subjects received amphotericin. Posaconazole was the only treatment in one immunosuppressed patient. All immunocompetent patients had single paranasal sinus disease and received only surgical treatment. All patients are alive and free of disease. They concluded that indolent mucormycosis is a new and emerging clinical entity in immunosuppressed and immunocompetent patients. Single paranasal sinus disease is a frequent presentation and should not be overlooked as a differential diagnosis in these patients. Immunocompetent patients should only be treated surgically [28].

Conclusion

Though rhino-orbito-cerebral mucormycosis is a rare, it’s a life threatening infection and is a medical emergency. Hence, timely diagnosis and debridement is needed with initiation of systemic amphotericin B. Multidisciplinary approach is needed for the management of mucormycosis. Results in our study showed significant morbidity like loss of vision but nil mortality. I conclude that early diagnosis and timely surgical intervention forms the corner stone of the disease management.

Funding

None.

Declarations

Confilct of interest

The authors declare that there is no conflict of interest.

Ethical Approval

Exempt as a retrospective study. Informed consent was obtained from study participants for surgical procedures and use of data for research purpose.

Consent to Participate

Not applicable, as it’s a retrospective study.