Periorbital Cellulitis Secondary to Conidiobolus Incongruus
Mary E. Temple, Pharm.D., Michael T. Brady, M.D., Katalin I. Koranyi, M.D., and Milap C. Nahata, Pharm.D., Colleges of Pharmacy and Medicine, The Ohio State University, and Children's Hospital, Columbus, Ohio
Abstract and Introduction
Abstract
A previously healthy, 18-month-old girl developed edema and erythema around her left eye 1 week after getting sand in that eye. The patient did not respond to oral or intravenous antibiotics. A mass developed around the eye, and biopsy revealed Conidiobolus incongruus. The patient failed to respond to amphotericin B 1 mg/kg, and susceptibility tests indicated multiantifungal resistance. A combination of antifungal therapy, hyperbaric oxygen, and surgery was required for successful treatment. Three months after treatment the child was disease free. There is no definitive therapy for Conidiobolus incongruus infections, although various drugs have been administered with some success. When susceptibility tests determine multidrug resistance, radical resection with antifungal chemotherapy and hyperbaric oxygen may be necessary as well as lifesaving.
Introduction
The genus Conidiobolus is a member of the fungal order Entomophthorales.[1] Species of Conidiobolus are found in nature as saprophytes and are usually weak pathogens of insects. Three species -- incongruus, lamprauges, and coronatas -- cause fungal disease in animals and humans.[2] The chronic, granulomatous, inflammatory infection usually affects healthy people and presents as a well-circumscribed subcutaneous mass typically involving the nasal and maxillofacial regions; the paranasal sinuses, however, also may be affected.[3]
Fungal infections due to Conidiobolus are rare, particularly in North America. These fungi have a geographic predilection for tropical and subtropical areas, primarily in parts of sub-Saharan Africa and Southeast Asia.[2] However, there were a few reports in North America.[3-6] Sixty percent of Conidiobolus infections occur in adults aged 20-29 years.[7] The disease is very uncommon in children. No children from North America and only one child with an infection involving the face were reported in the literature. Potassium hydroxide, hyperbaric oxygen (HBO), and antifungals such as amphotericin B, ketoconazole, and terbinafine were used to treat these patients.
Case Report
Our patient was an 18-month-old Caucasian girl with a medical history significant only for premature birth at 28 weeks' gestation. At that time, she required ventilatory support without significant complications or sequelae. The patient was in good health until the age of 18 months when she developed swelling and erythema of her left eye. The swelling was noted 1 week after getting sand in that eye. Her physician prescribed amoxicillin-clavulanate and sulfacetamide ophthalmic drops for an early preseptal cellulitis. Her symptoms worsened over the next 7 days, and the girl was taken to a local emergency department for evaluation. On physical examination, her temperature was 99.4°F (axillary). She had tender induration of the epicanthal region of the left eye, with swelling of the upper and lower eyelids, and yellow discharge from the eye. The conjunctivae were clear bilaterally, and the extraocular muscles were intact. She also had swelling of the left upper cheek and nasal bridge. The remainder of the physical examination was unremarkable.
The patient was admitted to the hospital with a diagnosis of periorbital cellulitis. Her white blood cell count on admission was 15,700 x 103/mm3, with a normal differential blood count. She was given cefotaxime and nafcillin intravenously. Computed tomography (CT) of the orbits revealed a mass of intermediate density near the nasal lacrimal duct, with displacement of the globe laterally. There was no evidence of a retro-orbital mass lesion, necrosis, or fluid collection. Clinically, the mass worsened, and patient was referred to our hospital for evaluation of the mass. The differential diagnosis was tumor versus inflammatory lesion such as dacrocystitis.
A biopsy of the mass revealed phycomycosis of the periorbital tissue. The eye had marked indurated erythema with a small amount of purulent drainage at the medial canthus. Concentrations of serum immunoglobulins IgM 230 mg/dl and IgE 192 mg/dl were slightly elevated and likely consistent with a fungal infection. Delayed hypersensitivity skin tests were positive, and CD3+, CD4+, and CD8+ cell counts were normal. Cultures were obtained from soil and water at the site where the child was exposed.
The girl was started on amphotericin B 1 mg/kg/day. After 1 week of treatment, the left eye had not improved. Possible causes of the persistent and worsening condition were resistance of fungi to amphotericin B and the breakdown of killed fungi with subsequent inflammatory reaction. A CT scan showed enlargement of the preseptal mass on the left side. The left ethmoid sinus was opacified with bony erosion laterally. The lacrimal duct also was blocked. There was no infiltration of the left globe or erosion of the nasal bone.
The patient underwent left endoscopic intranasal ethmoidectomy to remove the mass. Granulomatous tissue was removed from below the lower eyelid and sent for analysis. Amphotericin B 0.1 mg was injected into eight different sites in the subcutaneous tissue in and around the area where the mass had been removed. Natamycin 0.5% ophthalmic solution 1 drop 4 times/day and dexamethasone 2 mg orally every 12 hours were added to the patient's treatment regimen. Nine days after admission, the inflammation around the eye had decreased. Preliminary cultures from the biopsy showed Conidiobolus. The histology of the fungus revealed discrete focal lesions with fragments of fungal hyphae surrounded by Splendore-Hoeppli and acute inflammation. The background infiltrate was rich in reactive histiocytes and eosinophils. The fungal stain revealed thin-walled hyphae with rare septation and apparent right-angle branching. Specimens were sent to a fungus-testing laboratory at the University of Texas Health Sciences Center for confirmation and susceptibility testing. The inflammation and erythema continued to decrease around the left eye. On day 11 of treatment, the patient was discharged and prescribed amphotericin B and a dexamethasone taper.
One week later, the patient was readmitted due to fever, increased irritability, and edema and erythema of her left eye. On admission she was febrile (102.3°F axillary) and irritable. The left eye mass was hard, indurated, erythematous, and warm and had a central bluish hue (Figure 1). Her left eye was completely swollen shut.
Figure 1. (click image to zoom) The erythematous, indurated lesion with a necrotic area can be seen involving the medial portions of both the upper and lower eyelids.
A CT scan revealed an increase in the size of the mass compared with the CT scan 2 weeks earlier (Figure 2). There was also a mild increase in the posterior extension of the mass along the medial aspect of the left medial rectus muscle. The left maxillary sinus was more opaque superiorly compared with the previous CT scan. A new finding, not present on the previous scan, was a 1 x 2.5-cm, low-density collection of fluid or necrotic tissue just below the skin, anterior to the maxillary sinus. By this time, the fungus was identified as Conidiobolus incongruus, resistant to amphotericin B and all routinely available marketed antifungals.
Figure 2. (click image to zoom) A prominent soft-tissue mass is noted that involves the left premaxillary soft tissue and the preseptal portions of the orbit with extension along the medial aspect of the left medial rectus muscle and across the bridge of the nose. Neither the globe nor the orbital apex is involved.
Amphotericin B minimum inhibitory concentrations (MICs) were 4 µg/ml and 8 µg/ml at 24 and 48 hours, respectively, and minimum lethal concentrations were 8 µg/ml and 16 µg/ml at 24 and 48 hours, respectively. Ketoconazole MICs were 16 µg/ml and greater than 16 µg/ml at 24 and 48 hours, whereas flucytosine had an MIC of greater than 64 µg/ml at 24 hours. Itraconazole MIC data showed the most promise for this patient with MICs of 1 µg/ml and 8 µg/ml at 24 and 48 hours, respectively.
Because itraconazole had the lowest MIC (even though its MICs met the definition of resistance), treatment with oral itraconazole 100 mg/day was begun. Due to concern about intracranial involvement and extension to the contralateral eye, surgery was performed to remove all infected tissue. On excision, the inferior orbital rim, medial orbit at the level of the lamina papyracea, anterior ethmoid, and midcheek soft tissue were all found to be grossly infected with fungus. The patient underwent resection of the inferior turbinate, exoneration of the left orbit, left ethmoidectomy, and maxilectomy. The wound was irrigated and packed with fluconazole-impregnated vaginal packing.
The patient began postoperative HBO treatments once/day with itraconazole 100 mg/day (12 mg/kg/day) and amphotericin B 1 mg/kg/day. Hyperbaric oxygen treatment was given at 2.2 atmospheres of pressure while the patient breathed 100% oxygen, and was continued 6 times/week with weekly assessment of need for further treatment. Amphotericin B was stopped after a total dose of 30 mg/kg. Itraconazole was continued for 3 months. The patient's postoperative course was complicated by a Pseudomonas aeruginosa wound infection that was treated with ceftazidime and gentamicin. All repeat wound cultures at 1 and 2 months were negative. Follow-up CT scans did not show any recurrence. Three months after completing all therapy, the patient showed no evidence of recurrent fungal infection. Periorbital Cellulitis Secondary to Conidiobolus incongruus
Discussion
In this young child, Conidiobolus incongruus involving the left eye and paranasal sinuses that was resistant to antifungal therapy alone is the second reported case of an orofacial infection due to C. incongruus, and is the first reported from the United States. The previously reported case of orofacial infection with Conidiobolus involved a 9-year-old healthy boy, who experienced trauma to the left eye after falling off a bicycle.[13] In that case, the left lower lid became gradually larger and firmer. An orbital biopsy revealed C. incongruus, and amphotericin B 1 mg/kg/day was administered. Treatment with amphotericin, however, and later, oral itraconazole and miconazole, failed. The patient underwent radical resection of the left eye, left cheek and cervical lymph nodes. Unfortunately, despite radical resection, the infection recurred. The patient finally was treated with HBO using 2.2 atmospheres of pressure, intravenous trimethoprim-sulfamethoxazole 20/100 mg/kg every 6 hours, and miconazole 100 mg twice/day. After 49 hours of treatment, the infection resolved.
Our patient had the second reported case of orbitofacial infection due to C. incongruus, and represents the first pediatric case in North America. It is also the first reported case of paranasal sinus involvement with a multiresistant Conidiobolus species. Soil and water samples tested from the site where inoculation most likely occurred were negative. We still believe, however, that the sand that contacted her eye was the likely source of infection. The fungus then probably spread from the epicanthal region of the left eye into the paranasal sinuses and to the subcutaneous tissue in the left cheek.
The preferred methods of diagnosis of C. incongruus are biopsy for histology and tissue culture. Both were helpful in this case. The characteristic zygospores, prominent pointed papillae, and forcibly discharged conidia differentiated the species incongruus from coronatus.C. coronatus does not produce zygospores and has resting villous conidia.[9]
There is no definitive therapy for Conidiobolus infections, although trimethoprim-sulfamethoxazole, potassium iodide, amphotericin B, and some of the azoles (itraconazole, fluconazole and ketoconazole) have shown limited efficacy.[3-17] Clinical failure has been reported with all.
Surgical resection appeared to complement the benefits of HBO treatment, amphotericin B, and itraconazole in our patient. Hyperbaric oxygen treatment was effective in five reported patients, one involving C. coronatus infection in the maxillofacial region and four involving rhinocerebral mucormycosis.[14,15] Hyperbaric oxygen's fungistatic effects make it valuable in treating fungal infections.[16] It increases oxygen tension in unaffected surrounding tissue, which reduces tissue acidosis and inhibits fungal growth. It also may provide an additive effect with amphotericin B because the latter is most effective in an aerobic environment.[17] Since amphotericin B causes oxidative damage to fungal membranes, higher oxygen concentrations may potentiate its effects.
In our patient, amphotericin B 1 mg/kg/day was used initially with natamycin ophthalmic drops once a preliminary fungal etiology was identified. Liposomal amphotericin B was not used, as it has not been shown to work better than conventional amphotericin B (personal communication, J. Bennett, M.D., August 30, 1995).[13] When susceptibility tests indicated multiresistance to available antifungal agents, radical resection of the fungal mass followed by long-term itraconazole and HBO treatment was undertaken.
Medical management, when effective, is preferred. However, for lesions that are unresponsive to antifungal chemotherapy, HBOT and surgical resection may be necessary as well as lifesaving.
Reprinted with Permission
