Cutaneous Entomophthoromycosis from Bihar: A Report of Three Cases and Review of Literature

Sir,

Cutaneous entomophthoromycosis is endemic in the tropics and subtropical regions (southern India). It usually affects immunocompetent patients, and the infection is of two types: Basidiobolomycosis and conidiobolomycosis. The saprobes of the fungus are present in moist, decomposing, or rotting plant/vegetation and faecal matter of amphibians/reptiles. The infection is often preceded by trauma, although it can occur following inhalation of spores.[1] We are discussing three cases of entomophthoromycosis from Bihar, who presented with varied morphology and were diagnosed based on clinic-histopathological co-relation and successfully treated with a combination of supersaturated potassium iodide (SSKI) plus itraconazole therapy.

In our three cases, one infant and two adults presented with a localized hard plate-like swelling over the scrotum and face without any systemic involvement [Figures 1–3]. All were immunocompetent and given a prior history of trauma. Routine haematological investigations and inflammatory markers (ESR and CRP (Erythrocyte sedimentation rate and C reactive protein)) were within normal limits. Mantoux test was negative. The patients were diagnosed with cutaneous entomophthoromycosis based on clinic-histopathological correlation [Figure 4]. A tissue culture test was unavailable from the department of microbiology because of the COVID situation. Details of the clinical profile and investigation have been illustrated in Table 1.

Figure 1.

(a) Swelling on the central aspect of face covering entire nose, bilateral medical canthus, medial aspect of cheeks up to forehead (b) positive finger insinuation beneath the swelling (c) loss of skin pinchability on the surface

Figure 3.

(a) Well-defined swelling over scrotum with nodularity at places (b) positive finger insinuation beneath swelling (c) loss of skin pincability on surface

Figure 4.

(a and b) CT scan at different level showing soft tissue swelling involving perinasal region with no bony involvement (c) X-ray scrotum showing normal soft tissue

Table 1.

Clinical profile and treatment response and side-effect noted with itraconazole and SSKI of all the patients

	Case 1	Case 2	Case 3
Age/sex	37 years	42 years	9 months
Sex	Male	Male	Male
Duration of disease (months)	7	6	2
Risk factor	History of frequent nose picking	Road traffic accident	Crawling
Clinical finding	A firm to hard well-defined swelling on the central aspect of face covering entire nose, bilateral medical canthus, medial aspect of cheeks up to forehead [Figure 1a]. The surface was having mild scaling with colour ranging from erythematous to hyperpigmented. Finger insulation was possible beneath the swelling [Figure 1b] and the skin over the surface of swelling was not pinchable [Figure 1c].	Nasal polyp as initial presentation, followed by a hard subcutaneous plate-like mobile swelling over the left nasolabial region causing left nasal septum deviation with intermittent bleeding with faint erythema on surface, with loss of surface skin pinchability and insinuation of finger beneath swelling was positive [Figure 2a, b].	A hard plate-like, well-defined, non-tender swelling over scrotum [Figure 3a]. There were hard nodules on surface, insinuation of finger beneath swelling was positive; loss of skin pinchability on surface was there [Figure 3b, c]. Overlying skin had mild erythema.
Complication	Nasal obstruction, intermittent episodes of bleeding	Breathing difficulty from left nostril	None
On investigation
Radiological investigation	CT scan of head and neck: Soft tissue swelling without bony involvement [Figure 4]	CT scan of head and neck: Soft tissue swelling without bony involvement [Figure 4]	X-rays of scrotum: Normal without any calcification [Figure 4c]
Histopathology	Eosinophilic granulomatous tissue reaction pattern with and PAS-positive broad aseptate hyphae with Splendore–Hoeppli phenomenon [Figure 5]	Eosinophilic granulomatous tissue reaction pattern with and PAS-positive broad aseptate hyphae with Splendore–Hoeppli phenomenon [Figure 5]	Mixed granulomatous tissue reaction with eosinophilic infiltration and PAS-positive foreign body at the centre [Figure 5]
Treatment with itraconazole 5 mg/kg/day plus SSKI: Started with 54 drops (40 mg/kg/day) (18 drops TDS), dose increased 3/drops per day till end point
Duration for complete improvement:	10 weeks Tapered by 1/drop per day	8 weeks Subsequent tapering after complete improvement was done 1/drop per day	2 weeks
Maximum tolerated dose of SSKI	74 drops (24 drops TDS) till complete improvement	69 drops (23 drops TDS) for 2 weeks and later decreased to 21 drops TDS because of the side effects and continued till complete improvement	SSKI dose was fixed at 40 mg/kg/day because of being infant
Total duration of treatment	Itraconazole: 14 weeks SSKI: 22 weeks	Itraconazole: 10 weeks SSKI: 19 weeks	Itraconazole: 6 weeks SSKI: 6 weeks
Endpoint for SSKI	Metallic taste	Deranged thyroid profile	None

SSKI=supersaturated potassium iodide, PAS=periodic acid Schiff stain, CT=computed tomography, TDS

Figure 2.

(a) Erythematous to hyperpigmented swelling over left side of nose (b) positive finger insinuation

All the patients were treated with combination therapy of oral SSKI (dose: 40 mg/kg/day in three divided doses) and itraconazole 5 mg/kg/day. SSKI solution was prepared using KI salt dissolved in sterile water till no further crystals dissolved. One drop of SSKI solution contained approx. 50 mg KI. The dose of SSKI was increased daily until the endpoint was achieved. Clinical pointers for endpoint were lacrimation, metallic taste, and salivation. The biochemical pointer was a deranged thyroid profile. A baseline thyroid profile was done in all cases, along with weekly monitoring. The tapering of SSKI was done after complete improvement at a dose of 1 drop/day (50 mg/day). Itraconazole was continued for 4 more weeks after complete improvement. Liver function test (LFT) monitoring was done every month. Case 3 being infant, the dose of SSKI was maintained at a fixed dose 40 mg/kg/day. Complete improvement was seen in all cases [Table 1 and Figure 6]. Case 2 developed hypothyroidism after 2 weeks of treatment with SSKI, after which the dose was decreased, and the patient was started with a thyroxine sodium tablet of 50 micrograms. His thyroid profile was monitored and gradually returned to normal during 4 months.

Figure 6.

(a) Complete improvement of case 1 post-treatment (b) complete improvement of case 2 post-treatment (c) complete improvement in case 3 post-treatment

Figure 5.

(a) H and E stain: dense infiltrate in the lower dermis and subcutaneous layer ×4 (b) H and E stain: dense infiltrate and granuloma ×10 (c) H and E satin: Langerhans giant cells with lympho-histiocytes infiltrate along with eosinophiles ×40 (d) periodic acid Schiff stain: wide empty looking aeptate hyphae ×400 (red circle)

In the current case series, three immunocompetent patients of two adults and one infant, the adults had rhino-facial involvement suggestive of conidiobolomycosis and the infant had scrotum involvement suggestive of basidiobolomycosis. The clinical differentials of long-standing rhino-facial swelling include tuberculosis, leishmaniasis, sporotrichosis, soft tissue tumour, and lymphoma. Similarly, basidiobolomycosis may mimic other tropical infections presenting with subcutaneous swelling such as sporotrichosis, filarial elephantiasis and onchocerciasis, cutaneous tuberculosis, and other diseases, including Burkitt's lymphoma and soft tissue tumour.[2] However, histopathology can help in differentiating the above conditions.

There is no single best therapeutic agent for treatment. Various drugs tried include ketoconazole, itraconazole, fluconazole, potassium iodide, co-trimoxazole, and amphotericin-B. Considering the safety, easy oral administration, the efficacy of itraconazole and SSKI has been used in various reported cases. SSKI contains 1,000 mg of potassium iodide (KI) per ml, with each drop containing 50 mg and a density of 1.72 g/ml. It is stored in a light-resistant tight container at 15–30°C temperature. It is considered as a gold standard as it gets concentrated at the site of microorganisms and increases the myeloperoxidase enzyme activity of neutrophils and macrophages. It is given at a 40–60 mg/kg/day dose with a total of 3 g/day. It is contraindicated in hypersensitivity to KI, nodular thyroid disease, active tuberculosis, and low complement level. The common side effects are nausea, vomiting, and diarrhoea. Less common side effects are angioedema, urticaria, and iodism (burning in mouth, throat, metallic taste, lacrimation, headache, confusion, weakness, arrhythmia, numbness, eye swelling, and irritation).[3] The role of surgical resection is controversial, and surgery may hasten the spread of infection, according to Prasad et al.[4] All patients in our cases were started with an itraconazole dose of 5 mg/kg/day and a SSKI at 40 mg/kg/day. No patients developed deranged liver function tests in our case series, but one patient had deranged thyroid profiles, following which the dose of SSKI was decreased. All patients had complete improvement with the above treatment.

In a resource-poor setting, clinic-histopathological correlation and therapeutic response to treatment are sufficient to confirm the diagnosis of cutaneous entomophthoromycosis. On review of literature, there have been reports of cutaneous entomophthoromycosis from various parts of the world and India with different sites of involvement treated with various treatment regimes. The details of which have been illustrated in Supplementary Table 1.

Supplementary Table 1.

Literature review of Entomophthoromycosis

Authors	No of cases	Age in Years/sex	Duration	Location of lesion	Locality of patient	Morphology	Prior History of trauma	Treatment given	Outcome
Sackey et al.1	1	3/F	6 months	right leg, thigh and right buttock	Northern Ghana, West Africa	Diffuse Swelling And ulceration	Not available	itraconazole 5mg/kg with wound dressing and skin grafting	Significant improvement But lost to Follow up on 8th week
Chaiyasate et al.2	7	All males Mean age 53±15.7,	1 to 8 months	Face	Thailand	Asymptomatic Rhino-facial Swelling	Not mentioned	ITZ+KI+cotrimoxazole Or ITZ alone Or ITX+KI	Significant Improvement At 2 weeks to 10 month treatment
Anand M et al.3	1	3 Male	6 months	Left thigh	Maharashtra	Painless swelling Left thigh	Yes	ITZ+KI 6months	Complete improvement
Wankhade A B et al.4	2	18 F 37 M	6 and 4 months	Centre Of face	Chhattisgarh	Rhino-facial swelling		1.KI+ITZ for 2 Weeks and later Shifted to AmphotericinB 2. ITZ f/b amphotericinB f/b KTZ a	Responded Well to treatment
Thomas MM et al.5	1	6	12 months	Nose	Kerala	Asymptomatic Swelling Over nose	Not Mentioned	oral fluconazole+KI for 5 months	Completely improved
Arora P et al.6	1	2 year 6 Months	6 months	Left Buttock, Upper thigh	New Delhi	skin colored swelling	Yes	SSKI 1o weeks	Complete improvement
Thotan SP et al.7	1	10	3 months	Back	Manipal	Large subcutaneous swelling	Not mentioned	KI for 3 months	Complete Improvement
Verma RK et al.8	1	42, F	15 days	nape of neck and temporo- parietal region	Chandigarh	nontender firm swelling	Not mentioned	Intravenous amphotericin B deoxycholate for one and half month and oral potassium iodide for two month	Complete resolution

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