Rhinofacial Entomophthoromycosis: An Emerging Disease?

Abstract

Entomophthoromycosis, a rare subset of chronic subcutaneous fungal infection caused by Conidiobolus coronatus and Basidiobolus ranarum. It predominantly affects immunocompetent individuals, mostly men. It is typically seen in tropical countries. These case reports describe two male patients a 52-year-old and a 45-year-old from eastern India with a one-year history of rhino facial swelling, initially posing a diagnostic challenge. The skin biopsy revealed granulomas, multinucleated giant cells, and a positive Splendore-Hoeppli phenomenon, supported by MRI findings indicating soft tissue thickening and enhancement confirming the diagnosis. Both the patients were successfully managed with oral itraconazole and supersaturated potassium iodide which highlighted the importance of a comprehensive diagnostic approach and appropriate antifungal therapy.

Introduction

Entomophthoromycosis is a very rare sub-cutaneous fungal infection involving the skin and subcutaneous tissue. The causative agent is Conidiobolus coronatus, which predominantly affects the upper respiratory tract. This disease mostly presents in immunocompetent patients as opposed to other subcutaneous fungal infections that are common among immunocompromised.[1]

The complexity of this disease is that it masquerades many other infections such as atypical Mycobacterial, cellulitis, rhinoscleroma, lymphoma, lymphoedema, sarcoma, and other subcutaneous mycosis.[2] A high index of suspicion of this disease is required for evaluation, accurate diagnosis, and management of such cases. These case reports aim to provide valuable insights into the clinical presentation, diagnostic challenges, and effective therapeutic interventions associated with this fungal infection.

Case Reports

Case 1

A 52-year-old male from West Bengal, a farmer by occupation presented to our dermatology outpatient department with a history of progressive swelling of the nose, cheeks, and forehead for about 6 months. He also had difficulty in opening mouth and mild dysphagia. The patient had no significant immunocompromising conditions, chronic illness, or past history of local trauma.

Clinical examination revealed diffuse, firm, mildly tender, indurated subcutaneous swelling involving the external nose, bilateral malar prominence more in the left side and central aspect of the forehead [Figure 1a]. Notably, the prominence of the philtrum due to underlying swelling was evident, accompanied by the obliteration of the nasolabial fold [Figure 1b]. The overlying skin appeared normal. The oral mucosa was healthy. There was no regional lymphadenopathy.

Figure 1.

(a) Baseline case 1 (Frontal view): Diffuse, firm and indurated subcutaneous swelling involving the external nose, bilateral malar prominence more in the left side and central aspect of the forehead. Prominence of the philtrum due to underlying swelling was evident, accompanied by the obliteration of the nasolabial fold. (b) Baseline case 1 (Lateral view of the patient)

Case 2

A 45-year-old male from northern Odisha, a farmer by occupation came with a history of progressive facial swelling involving the nose, bilateral cheeks, upper lip, left nostril, and forehead for about 12 months. He was facing difficulty in opening his eyes and mouth due to gross subcutaneous swelling. The patients had no immunocompromising condition, chronic illness, or history of local trauma.

Clinical examination revealed diffuse, indurated, firm to hard subcutaneous swelling, involving the external nose, malar, infraorbital, and central part of the forehead [Figure 2a]. The prominence of the philtrum was quite evident due to underlying swelling [Figure 2b]. The overlying skin was normal but not pinchable. Oral mucosa was healthy without any regional lymphadenopathy.

Figure 2.

(a) Baseline case 2 (Frontal view): Diffuse, indurated, firm to hard subcutaneous swelling, involving the external nose more on the left side, with involvement of both malar regions, periorbital and central part of the forehead. With a typical “‘Hippopotamus Facies”’ appearance. (b) Baseline case 2 (Lateral view)

The facial deformity resembled the classical “Hippopotamus Facies” in both cases.

A punch biopsy from the forehead was performed and the crushed tissue was sent for KOH mount, fungal culture, and histopathological examination in both cases. To further elucidate the nature of the swelling, a contrast-enhanced MRI of the nose and paranasal sinuses was performed showing homogenous enhancement and soft tissue thickening of the external nose, upper lip, nasolabial fold, and left side of the face. Involvement of the inferior turbinate was noted in the first case. The MRI findings were suggestive of an infectious pathology. An otorhinolaryngology consultation was also taken.

The KOH mount showed broad, ribbon-like pauci septate or aseptate hyphae with variable angle of hyphal branching morphologically resembling presence of fungal elements of family Zygomycetes; however, no growth was detected on fungal culture [Figure 3]. The histopathological examination of the specimens revealed multiple granulomas with a significant number of multinucleated giant cells, plasma cells and eosinophils. A positive Splendore-Hoeppli phenomenon further supported the diagnosis of entomophthoromycosis [Figures 4a-c].

Figure 3.

KOH mount of the tissue from the lesion showing broad, ribbon-like pauci septate or aseptate hyphae with variable angle of hyphal branching

Figure 4.

(a) H&E stain, 40×: Section shows fibro-connective tissue showing diffuse infiltration of polymorphs, lymphocytes, plasma cells, eosinophils. (b) H&E stain, 40×: Section shows focal areas of eosinophilic acellular material surrounded by dense infiltration of histiocytes along with multinucleated giant cells with focal areas of granulations with Splendore Hoeppli phenomenon. (c) H&E stain, 4×: Shows epidermis and dermis with above findings focal areas of eosinophilic acellular material surrounded by dense infiltration of histiocytes along with multinucleated giant cells with focal areas of granulations

Based on the clinical, microbiological and histopathological evidences, both the cases were diagnosed as entomophthoromycosis. The baseline investigations i.e complete blood count, renal function test, liver function test, ECG, thyroid function test, HIV 1 and HIV 2 were within normal limits. Oral itraconazole at a dose of 200 mg twice daily for a period of 2 months along with super-saturated potassium iodide solution was started, followed by oral itraconazole for 4 months.

The oral super saturated potassium Iodide solution was prepared with 1gm of potassium iodide crystals in 1 mL of Distilled water (20 drops). The dose was titrated considering the adverse effects, initially starting with 3 drops thrice daily (1 drop = 67 mg of potassium iodide) and progressively increasing up to 20 drops based on tolerance and signs of excessive lacrimation, nasal discharge and gastrointestinal side effects. The patients were given 3 drops thrice daily for first two week, then increased gradually at an escalating dose of 4 drops thrice daily in the next 2 weeks, with a maximum up to 18 drops daily.[3]

The response of treatment was clinically assessed by measuring head circumference and extent of induration before medication, then after 1 week, and two months of treatment [Table 1]. The assessments demonstrated a notable reduction in swelling and resolution of symptoms within a few days of medication which showed a favourable response to two drugs antifungal therapy and a marked improvement in their quality of life. Thus, strengthening the diagnostic accuracy and to continue the treatment further [Figures 5a-d].

Table 1.

Improvement in the circumferential measurement of swelling at 4 marked sites of the face-at baseline, week 1 and 2 months

Site Case	Baseline		Week 1		2 months
	1	2	1	2	1	2
Forehead	20 inches	22 inches	19.7 inches	21.8 inches	18.5 inches	21.5 inches
Bridge of the nose	19.4 inches	22.2 inches	19 inches	22.2 inches	18 inches	21 inches
Tip of nose	21 inches	23 inches	19 inches	21 inches	18 inches	20.8 inches
Philtrum	24 inches	22.2 inches	22 inches	20.9 inches	21.5 inches	19.5 inches

Figure 5.

(a and b) Case 1- Noticeable improvement 2 months after drug therapy. (Frontal view and lateral view) . (c and d) Case 2- Significant reduction and marked improvement in the swelling 2 months after drug therapy (Frontal view and lateral view)

Discussion

Entomophthoromycosis is a subcutaneous fungal infection. “Entomon” in Greek refers to an insect which implies these fungi were originally thought to be parasites infecting insects. Primarily found in tropical and subtropical regions, affecting immunocompetent hosts, with males more frequently affected than females.[4]

The Entomophthorales order includes six families: Ancylistaceae, Basidiobolaceae, Completoriaceae, Entomopthoraceae, Meristacraceae, and Neozygitaceae.[5] Genus Basidiobolaceae has four species, most common of which is Basidiobolus ranarum, causes basidiobolomyocis, affecting limbs, trunk, buttocks, and gastrointestinal system in immunocompetent and immunocompromised individuals. Conidobolomycosis, caused by Conidiobous coronatus, leads to chronic rhinofacial subcutaenous infection, causing disfigurement in immunocompetent hosts. Notably, C. coronatus and B. ranarum are the principal species linked to medical instances of entomophthoromycosis.[6]

Entomophthoromycosis develops by means of inhalation of spores causing sinus disease or through cutaneous inoculation. These fungi are of very low virulence as manifested by rare occurrence of this disease despite widespread prevalence. Most cases are usually reported from India and sub-Saharan Africa. Clinical manifestations include subcutaneous swelling which is very firm to hard in consistency, well defined, sometimes satellite lesions can be palpated at the advancing margin of lesions. Overlying skin can be intact, tense oedematous or hyper pigmented or normal in colour and skin texture, similar to the description of our cases.[7]

It can mimic atypical Mycobacterial infection, cellulitis, rhinoscleroma, lymphoma, lymphoedema, sarcoma and other subcutaneous mycosis. It can also spread to adjacent bones, paranasal sinuses, lung and mediastinum, extend to orbital cavity resulting in proptosis and vision loss.[1] In our cases, there was involvement of paranasal sinuses with no evidence of systemic involvement.

Direct potassium hydroxide mount (10% KOH) reveals the typical broad, ribbon-like aseptate hyphae with acute angle of hyphal branching. may be confused with Mucorales. Hence, diagnosis is mainly done by means of histopathological examination revealing chronic granulomatous inflammation with eosinophils, histiocytes, foreign body giant cells the so called Splendore Hoeppli phenomenon was evident in our cases.[8] Splendore Hoeppli phenomenon is an in-vivo formation of intensely eosinophilic material in a flower like radiating pattern around the fungal elements is typically seen in Entomophthoromycosis and not seen in mucormycosis, rather it may have leucocytosis and peripheral eosinophilia.[8] Serological detection of B. ranarum antibodies by ELISA/immunodiffusion have been reported with 100% sensitivity and specificity but are not widely available.[9,10]

Next generation sequencing (NGS) is no doubt a better option for diagnosing fungal infection because of difficulty in culturing, delay in growth and low fungal load as compared to bacterial and viral infection. However, NGS result require bioinformatics analysis for interpretation, which needs additional equipment, knowledge, training and cost as well. Further, unlike conventional microscopy and culture, NGS data cannot be directly applied to clinical decision-making and selecting the appropriate antimicrobial, rather, the NGS results are more useful for epidemiological study.[11] Thus, despite the availability of advanced molecular diagnostic tools, conventional techniques still have an essential role in routine clinical fungal diagnostics.[12]

Treatment with oral itraconazole, potassium iodide, amphotericin B, imidazoles and surgical modalities have been reported to be successful.[13] Mendiratta et al.,[14] reported poor response with single drug itraconazole when compared to the combination of itraconazole and potassium iodide which showed significant improvement. Chandaram et al.,[15] study suggests oral itraconazole and SSKI for rapid response and 4 months of monotherapy (oral itraconazole) preventing delayed recurrence. Contraindications include pregnancy, hypersensitivity, and acute infections like Tuberculosis or bronchitis. Dose-limiting adverse reactions include hypothyroidism, parotitis, acneiform skin eruptions, nausea, or vomiting.

Our patient’s favorable response to oral itraconazole and SSKI supports the two-drug regimen and its efficacy in the management of rhinofacial entomophthoromycosis. However, the documented risk of relapse in such cases necessitates regular follow-ups for longer periods.

Conclusion

This case report highlights our clinical exploration of an unusual rhinofacial swelling, eventually identifying it as a rare fungal infection, entomophthoromycosis. Both of these instances were reported within a period of one month, indicating a probable growing incidence and/or underreporting. The importance of a comprehensive diagnostic strategy includes a high degree of suspicion and meticulous testing. The two-drug therapy resulted in a significant early improvement. An increased awareness among clinicians is crucial for the timely recognition and appropriate treatment, particularly in regions where its prevalence is higher.

Author contributions

BB: Concepts, design, definition of intellectual content, literature search, clinical studies, manuscript preparation, manuscript editing, manuscript review, guarantor. SC: Concepts, design, definition of intellectual content, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, manuscript review, guarantor. MSK: Concepts, design, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript review. CKS: Concepts, design, definition of intellectual content, literature search, clinical studies, data acquisition, manuscript editing, manuscript review.

Conflict of interest

There are no conflicts of interest.

Funding Statement

Nil.