Tropical medicine rounds Aprospectivecaseseriesevaluatingefficacyandsafetyof combination of itraconazole and potassium iodide in rhinofacial conidiobolomycosis

Manish Gupta1, MS, Tarun Narang2, MD, Rupinder Jeet Kaur3, MD, Ashwani Manhas4, MD, Uma Nahar Saikia5, MD, and Sunil Dogra2, MD, MANAMS, FRCP

1Department of ENT, Gian Sagar Medical Abstract College & Hospital, Banur District, Patiala, Background Rhinofacial conidiobolomycosis (RFC) is an uncommon subcutaneous fungal 2 Punjab, Department of Dermatology, infection producing painless swelling with grotesque deformity of the face. Although there Venereology and Leprology, Post Graduate are case reports and small case series; there are very few prospective studies evaluating Institute of Medical Education & Research, Chandigarh, 3Department of Pathology, treatment outcome and long-term follow-up. Gian Sagar Medical College & Hospital, Objective To evaluate the safety and efficacy of combination of itraconazole (200 mg Banur District, Patiala, Punjab, twice daily) and saturated solution of potassium iodide (SSKI) in patients with RFC. 4 Department of Microbiology, Gian Sagar Methods Ten patients of RFC were studied over a period of 5 years. Diagnosis was Medical College & Hospital, Banur District, confirmed by clinical, histopathological, and microbiological evaluation. Conidiobolus was Patiala, Punjab, and 5Department of Histopathology, Post Graduate Institute of cultured in four cases and in the rest of the cases, the histopathology was suggestive of Medical Education & Research, RFC. They were treated with itraconazole (200 mg twice daily) and SSKI and followed up Chandigarh, India for a minimum of 1 year after stopping treatment. Results The mean age was 38.7 years and the mean duration of symptoms was Correspondence 22.4 months. Males were predominantly involved (9 : 1). Seven patients responded to Tarun Narang, MD Assistant Professor the combination treatment, five had complete resolution and two had good improvement Department of Dermatology, Venereology (50–75%); however, in two patients the response was minimal (<25% regression of the and Leprology swelling) and one patient did not show any improvement after 6 months of treatment. Post Graduate Institute of Medical Conclusion Combination of itraconazole and SSKI is an effective treatment modality for Education and Research RFC with relatively faster onset of action, low relapse rates, and minimal adverse effects. It Chandigarh 160012 India can be considered as first-line treatment in patients with RFC. E-mail: [email protected]

Conflicts of interest: None.

The paper was presented in the Commonwealth session of the Annual Meeting of the British Association of Dermatologists 2014 in Glasgow doi: 10.1111/ijd.12966

and pain due to extension to the paranasal sinuses.3,4 Introduction Clinically the extent of involvement can be divided into Rhinofacial conidiobolomycosis (RFC) or subcutaneous three phases. In phase I, involvement is limited to the zygomycosis or rhinoentophthoromycosis is a chronic nasal cavity, paranasal sinuses, and pharynx. In phase II, granulomatous fungal infection involving the mucosa and infection extends to the surrounding subcutaneous tissues, subcutaneous tissues of the nose and face. It is caused by causing facial swelling with involvement of the lips. In Conidiobolus, a saprophytic fungus that is ubiquitous in phase III, muscles, bones, and viscera are affected.4 distribution and is transmitted by traumatic inoculation of Despite the ubiquitous distribution of the fungus, RFC the nasal mucosa with dust or soil containing spores.1,2 is relatively uncommon with approximately 199 cases The infection begins as a swelling of the inferior turbin- reported worldwide.4,5 There are very few/small case ser- ates, with symptoms of nasal obstruction, nasal discharge, ies and no prospective studies evaluating the treatment 1

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outcome and follow-up of these cases.5–10 Therefore, we Non-contrast computed tomography showed soft tissue endeavored to undertake a prospective study of these swelling of the nasal dorsum and nasal cavity tissues in cases and their management at our centers. all the patients, and all the sinuses were opacified with soft tissue mass in four patients with facial elephantiasis. Extra sinus extension to adjacent soft tissue was also Methods seen, but there was no bone erosion. This was a prospective study of 10 cases of RFC seen at The histopathology was consistent with RFC in all the our centers during a span of five years (2008–2012). The patients with features of chronic granulomatous dermati- diagnosis in all the cases was confirmed after histopathol- tis in the deep dermis. The inflammatory infiltrate was ogy and culture from nasal mucosa and skin. All the composed of histiocytes and eosinophils. Twisted and patients were started on itraconazole 200 mg twice a day collapsed hyphae with irregular branching and Splen- and saturated solution of potassium iodide (SSKI) 1 g/ml dore–Hoeppli phenomenon were seen in six cases (i.e., 1 drop = 67 mg) starting with five drops thrice a (Fig. 4). KOH preparation of nasal biopsy tissue revealed day, which was gradually titrated to a maximum of 30 broad, aseptate, thin-walled ribbon-like hyphae with drops thrice a day depending on patient tolerance. All the wide-angle branching in three cases, and culture on patients were given the treatment for a minimum of Sabouraud’s agar was positive (Conidiobolus) in four three months; if the patient had >25% improvement, the cases. treatment was continued until two months after clinical Seven patients responded to treatment; five had com- improvement and in case of no response, alternative drugs plete resolution with almost complete disappearance of were offered to the patients. The treatment response and facial/nasal swelling (Fig. 5), and two had good improve- adverse effects were monitored every month during ther- ment (50–75%) (Fig. 6); however, in two patients the apy and the patients were followed up for a minimum of response was minimal (<25% regression of the swelling), one year after stopping the treatment. and one patient did not show any response after three months of combination. All the seven patients with significant improvement started responding after Results two months, and therapy was continued until 6– The clinico-epidemiological details and therapeutic out- 9 months. None of these patients relapsed in the 1– come are given in Table 1. All the patients were from rural 2 years of follow-up. and semi-urban areas in and around the Punjab. The age of At the end of six months, the patients with minimal the patients ranged from 24 to 65 years (mean age response had negative fungal culture and periodic acid 38.7 years); the mean duration of illness was 22.4 months Schiff stain, but histopathology showed changes sugges- (6–48 months). All the patients were engaged in agricul- tive of chronic mixed inflammation with fibrosis. Ampho- tural or outdoor occupations, and the initial symptoms tericin B was started in two of them who improved were nasal (discharge and pain); however, patients could significantly after one month of therapy, but they were not recall history of trauma before onset of symptoms/ unable to continue due to financial constraints, and both signs. The patients presented to us with an asymptomatic relapsed after stopping it. They were continued on SSKI gradually progressive, firm to hard sharply demarcated, and fluconazole 200 mg/d for six months, which stabi- subcutaneous indurated swelling on the dorsum of the nose lized the swelling, and then patients were lost to follow- and adjoining cheek area (Figs. 1 and 2), and four patients up. One patient did not respond to the combination treat- presented with facial elephantiasis (Fig. 3). In patients with ment, could not afford amphotericin B or Voriconazole, minimal swelling of the nose, anterior rhinoscopy showed and stopped coming for follow-up. We observed that lateral nasal wall diffuse swelling and inferior turbinate patients with facial elephantiasis had a less satisfactory hypertrophy. There was no significant lymphadenopathy, response as compared to those without it (Table 2). All and the systemic examination was normal in all the patients with facial elephantiasis had residual deformity patients. Complete blood counts showed eosinophilia in after treatment and were advised reconstructive surgery. seven patients (differential eosinophil count; 10–25%); the Adverse effects associated with itraconazole and SSKI rest of the parameters and biochemistry were normal. were seen in five patients. These were nausea, vomiting, Serology for human immunodeficiency virus was negative. diarrhea, abdominal pain, and transiently increased hepa- Almost all the cases had consulted various specialists, and tic enzyme levels. Two patients developed acneiform five had undergone surgery after they were diagnosed as eruption. The gastrointestinal complaints improved after polyps and fungal sinusitis. All had received various antibi- a decreasing dose of SSKI and transaminitis (elevated otics earlier but with no improvement; however, none were hepatic enzymes) improved after decreasing the dose of using local or systemic steroids/immunosuppressants. itraconazole from 400 to 200 mg/d.

International Journal of Dermatology 2015 ª 2015 The International Society of Dermatology ª Gupta 2015 ta.Rioailcndoooyoi:apopciecs series case prospective a conidiobolomycosis: Rhinofacial al. et h nentoa oit fDraooyItrainlJunlo Dermatology of Journal International Dermatology of Society International The

Table 1 Demographic and management details of the patients

Duration of Duration History of treatment Response at end Age/sex of disease nasal surgery Culture Treatment (months) of treatment Follow-up

1 28/M 8 months No Conidiobolus Itraconazole and SSKI 6 Complete resolution 2 years. No relapse/deformities 2 56/M 2 years No Conidiobolus Itraconazole and SSKI 9 Complete resolution 3 years. No relapse/deformities 3 41/F 1 year No No growth Itraconazole and SSKI 6 Complete resolution 1 year. No relapse/deformities 4 30/M 2 years No No growth Itraconazole and SSKI 6 Complete resolution 2 years. No relapse/deformities 5 32/M 1 year No Conidiobolus Itraconazole and SSKI 6 Complete resolution 1.5 years. No relapse/deformities 6 54/M 3 years Yes/removal of Conidiobolus Itraconazole and SSKI 9 50–75% improvement 1 year. Minimal persistent hypertrophied lymphedema inferior turbinate 7 24/M 1.5 years Yes/ No growth Itraconazole and SSKI 12 50–75% reduction 2 years. Residual persistent polypectomy in swelling lymphedema 8 27/M 2 years Yes No growth Itraconazole and SSKI 6 25% improvement 1 year. Responded to amphotericin. SSKI with fluconazole 6 Relapsed after stopping amphotericin B, Persistent swelling 9 30/M 1.5 years Yes (FESS) No growth Itraconazole and SSKI 6 25% improvement 1 year. Relapsed after responding to SSKI with fluconazole 6 in swelling amphotericin B, persistent swelling 10 65/M 4 years Yes/FESS No growth Itraconazole and SSKI 6 No improvement Lost to follow-up in swelling Persistent lymphedema; non-progressive

FESS, functional endoscopic sinus surgery; SSKI, saturated solution of potassium iodide. rpclmdcn rounds medicine Tropical 2015 3 4 Tropical medicine rounds Rhinofacial conidiobolomycosis: a prospective case series Gupta et al.

Figure 1 Stereotypical rhinofacial conidiobolomycosis with swelling over the nose, glabella, and cheeks Figure 3 Extensive facial involvement and disfigurement (facial elephantiasis)

Figure 4 Histopathological picture showing a mixed granuloma with Splendor–Hoeppli phenomenon Figure 2 Swelling of the dorsum of nose, glabella, and (hematoxylin and eosin, 920) extension to cheeks

underlying bone, and sinus formation leading to mutila- Discussion tion, no case of a mutilating, progressive course was seen Rhinofacial conidiobolomycosis is a progressive subcuta- in our study. neous granulomatous infection caused by C. coronatus, The initial and most common symptom is unilateral C. incongruus, and C. lampraugesa. It is generally divided nasal obstruction, mass, or discharge. Patients usually into four subtypes (Table 3). Clinical features start with present to otorhinolaryngology (ENT) specialists, and unilateral nasal stuffiness followed by swelling of the nasal examination may show indolent swelling of the nose, nasolabial folds, cheeks, lips, and neck. Subse- nasal mucosa, particularly the inferior turbinates with quently, symptoms of dysphagia and nasal obstruction polyps and mucopurulent discharge. Biopsy or nasal supervene, and rarely the palate, paranasal sinuses, and smear for KOH/culture at this stage can help in early pharynx may be involved. The most serious impact of the diagnosis and initiation of treatment, which can prevent disease is the gross disfigurement and pressure effects of deforming facial elephantiasis. The characteristic subcuta- the swelling on adjacent tissues. Although there are neous swelling on the face appears later and although it reports of a progressive destructive course of the disease has a very distinctive clinical picture, it may be misdiag- with necrosis of the overlying skin, involvement of the nosed sometimes due to rarity and unfamiliarity with the

International Journal of Dermatology 2015 ª 2015 The International Society of Dermatology Gupta et al. Rhinofacial conidiobolomycosis: a prospective case series Tropical medicine rounds 5

Figure 5 Pre- and post-treatment images, with complete resolution of the facial swelling after 6 months of treatment after combination therapy

because cultures for the causative organism are negative in more than 85% of cases.4,5 In our study as well, we could isolate the fungus only in 40% of the cases. The treatment of RFC has not been well-defined because the disease is infrequently reported. Although a number of antifungals have been used and reported as effective; the choice of the best antifungal agent, its dos- age and duration are unclear.4 Daily high-dose antifungal therapy and months of continuous treatment are required for successful management, and this may sometimes be difficult due to poor compliance resulting from adverse 3,4,8,11 Figure 6 Pre- and post-treatment image of a patient with effects and drug cost. Many antifungal drugs, such facial elephantiasis showing good clinical improvement after as SSKI, amphotericin B, imidazole derivatives (fluconaz- combination therapy ole, ketoconazole, terbinafine, and itraconazole), or a combination of these drugs,2,4,7–13 have been used for the disease. This was seen in five of our cases too, who were treatment of RFC with variable results. The available lit- misdiagnosed as cellulitis, nasal polyps, abscess, and fun- erature shows considerable variations in antifungal sus- gal sinusitis, and had undergone surgery. ceptibility in diverse isolates of C. coronatus. Two studies Clinically, it should be differentiated from rhinosclero- reported antifungal susceptibilities of six isolates of ma, rhinosporidiosis, lymphedema, benign and malignant C. coronatus against amphotericin B, ketoconazole, mico- tumors, and lymphoma of the nasal cavity;3 therefore, nazole, fluconazole, and flucytosine, and all the isolates mycological and histological examinations are essential for were resistant to the antifungals tested.14,15 In another confirmation of diagnosis. The diagnosis of Conidiobolus study, three isolates of C. coronatus showed very low infection is generally based on histologic examination MIC and MFC values against amphotericin B.16 Our

Table 2 Difference in the clinical features and treatment outcome of patients with facial elephantiasis vs stereotypical rhinofacial conidiobolomycosis

Facial elephantiasis Stereotypical

Number 4 6 Duration of illness Mean 33 months; median 24 months (24–48 months) Mean 22.4 months; median 12 months (range 6–48 months) Previous nasal surgery 3 2 Response Excellent – 05 Good – 11 Minimal – 20 No improvement – 10 Drugs SSKI, itraconazole, amphotericin B SSKI and itraconazole

SSKI, saturated solution of potassium iodide.

ª 2015 The International Society of Dermatology International Journal of Dermatology 2015 6 Tropical medicine rounds Rhinofacial conidiobolomycosis: a prospective case series Gupta et al.

Table 3 Four subtypes of rhinofacial conidiobolomycosis responded better than the patients with >2 years of disease duration and previous nasal/sinus surgeries. In the Stereotypical Nasal symptoms of obstruction, present study, the combination of itraconazole and SSKI nasal mass, coryza or epistaxis, was effective in 70% of patients. There are no controlled and/or central facial swelling Facial elephantiasis Gross facial disfigurement and loss of trials comparing various antifungals with each other or function superimposed on stereotypical type combination with monotherapy. Although synergistic Atypical Facial involvement other than nasal mucosa/ antifungal activity between these drugs has not been pro- skin or infection of another cutaneous ven, we presume that combination therapy is a better site (i.e., foot) option and further studies are warranted to determine the Systemic Non-cutaneous/non-sinus fungal infection true efficacy of these combinations. There is no consensus about the duration of treatment, but it must be continued for at least six months or until >75% reduction in swell- ing. patients responded favorably to SSKI and oral itraconaz- Our study has shortcomings, such as small sample size ole; however, the response was not uniform and univer- and no controls/comparison with monotherapy, which sal. Two patients had minimal improvement, and one need to be addressed in future studies. We observed that was non-responsive to the combination treatment. a combination of itraconazole and SSKI is an effective SSKI is a useful option for patients in developing coun- treatment modality with a relatively faster onset of tries because it is cheap, safe, gets localized to site of action, low relapse rates, and minimal adverse effects. It inflammation, and has fibrinolytic activity as well as can be considered as first-line treatment in patients with 4,8 indirect antifungal effects. However, we have RFC. Treatment should be started early to avoid compli- observed that the treatment response with SSKI is delayed cations such as facial elephantiasis and obstruction and to (4–6 months), and this slow response along with adverse decrease the cost of treatment as well as the morbidity. effects causes a high attrition rate; so we decided to com- bine SSKI with itraconazole to expedite the clinical response rate. Itraconazole, besides its excellent antifungal References activity, also has anti-tumorigenic effects, inhibits angio- 1 Krishnan SG, Sentamilselvi G, Kamalam A, et al. genesis, increases interferon c and affects the hedgehog Entomophthoromycosis in India: a 4-year study. Mycoses pathway, which may play a role controlling the inflamma- 1998; 41: 55–58. tion and swelling in RFC.17,18 The mean duration of ther- 2 Sugar AM. Agents of mucormycosis and related species. apy in our patients was 8.7 months. Although relapses In: Mandell GL, Bennett GE, Dolin R eds. Mandell, have been reported after successful treatment of swelling, Douglas and Bennett’s. Principles and Practice of we did not observe any relapse in seven patients with good Infectious Disease, 6th edn. New York: Churchill Livingstone, 2005: 2973–2984. to excellent response in the 1–3 years follow-up. 3 Prabhu RM, Patel R. Mucormycosis and Two patients with minimal response (<25%) had good entomophthoromycosis: a review of the clinical response to amphotericin B. However, RFC is a localized manifestations, diagnosis and treatment. Clin Microbiol non-life-threatening infection, and amphotericin B is not Infect 2004; 10: 31–47. commonly used because of the toxicity, inconvenience of 4 Isa-Isa R, Arenas R, Fernandez RF, et al. Rhinofacial administration, and due to cost. conidiobolomycosis (entomophthoramycosis). Clin Surgical resection is seldom helpful in the initial Dermatol 2012; 30: 409–412. stages of the disease as it may hasten the spread of 5 Choon SE, Kang J, Neafie RC, et al. Conidiobolomycosis infection and causes mutilation and fibrosis, which fur- in a young Malaysian woman showing chronic localized ther leads to poor response to treatment and relapses.3,4 fibrosing leukocytoclastic vasculitis: a case report and Five of our patients had undergone nasal/sinus or facial meta-analysis focusing on clinicopathologic and therapeutic correlations with outcome. (incision and drainage) surgery before the diagnosis, and Am J Dermatopathol 2012; 34: 511–522. three of these patients had poor response/relapsed after 6 Leopairut J, Larbcharoensub N, Cheewaruangroj W, stopping treatment. However, facial reconstructive sur- et al. Rhinofacial entomophthoramycosis; a case series gery is useful in patients with residual deformity after and review of the literature. Southeast Asian J Trop Med treatment. Public Health 2010; 41: 928–935. Successful management of infections relies on early 7 Maiti PK, Bose R, Bandyopadhyay S, et al. diagnosis; we found that the patients who were diagnosed Entomophthoromycosis in South Bengal (Eastern India): a within one year of the disease and had not undergone 9 years study. Indian J Pathol Microbiol 2004; 47: 295– any surgical procedures before the initiation of treatment 297.

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