Orbitofascial Conidiobolomycosis in a Child

Conidibolus incongruus, of the family order Entomophthorales, family Ancylistaceae,1 is a fungus that rarely causes infections in humans. Reported cases involved deep structures such as lung, mediastinum, heart, liver and gastrointestinal tract. The first fatal case of disseminated entomophthoramycosis caused by C. incongruus was reported in 1983.2 The present case is an unusual presentation of progressive infection within the orbit and subcutaneous tissue of the face in a previously healthy Saudi child. Our successful management of the infection, in which a new combination of therapies was used, prompted the case report and review of this fungal infection in children. Case report. A 9-year-old previously healthy boy from Shamran, a small town in the south of Saudi Arabia, first came to King Faisal Specialist Hospital and Research Centre on September 21, 1995, because of progressive proptosis of the left eye for 8 weeks. His father reported that his child developed a localized, firm, painless swelling over the lower lid of the left eye in mid-July 1995. The swelling began a few days after minor trauma to the left eye in which the child fell off his bicycle while playing on a neighboring dirt road, and some material from the ground entered his eye. The lower lid swelling became gradually larger and firmer with progressive proptosis of the left eye. The child denied orbital pain, visual problem, headache or fever. There was weight loss of 3 kg in 8 weeks. He was seen in several local clinics and was given local ophthalmic antibiotic ointment for the eye without improvement. On September 19, 1995, he was admitted to King Khaled Eye Specialist Hospital in Riyadh. An orbital mass biopsy showed necrotic granulomatous inflammation with fungal hyphae, and the patient was transferred to King Faisal Specialist Hospital and Research Center. At the time of admission the patient complained of retroorbital pain and headache. Physical examination revealed a pale-looking child. He was afebrile but had severe left eye proptosis. Ophthalmic examination revealed visual acuity 20/25 in the left eye and 20/20 in the right eye. The right eye was normal and the left eye demonstrated a superior laterally displaced globe with ≈12 mm proptosis. There was a large, firm, solid, nontender mass in the lower lid pressing the globe against the superior lateral orbital rim. The overlying skin was normal. There was no significant cervical lymphadenopathy. The remainder of the physical examination was unremarkable. Admission laboratory data included the following values: hemoglobin 12.2 g/dl; hematocrit 36%; white blood cell count 6600/mm3 with differential of 53% segmented neutrophils, 36% lymphocytes, 7% monocytes and 3% eosinophil. Platelet count was 607 000/mm3; hemoglobin electrophoresis was consistent with sickle cell trait. The erythrocyte sedimentation rate was 79 mm/h (Westergren). Renal profile, total serum protein values, liver function test and cerebrospinal fluid profile were within normal limits. The bone marrow aspiration and biopsy revealed normocellular marrow with active hemopoiesis and increase in the numbers of megakaryocytes. Roentgenographic examination of the chest and bone scan were normal. A computerized tomography scan and magnet resonance imaging of the left orbit and cranium revealed a large infiltrative process of the left orbital cavity which most likely arose from the lower lid region extracranially and showed significant displacement of the orbital contents and stretching of the optic nerve. There was also extension into the subcutaneous tissue around the orbital cavity. An excisional biopsy from the left orbital mass was submitted for histologic examination and culture. The microscopic examination showed multiple epithelioid granulomas with giant cells arranged around fungal hyphae and spores with intense eosinophilic infiltrate within the central portion of the granuloma (Fig. 1), a manifestation known as Splendore-Hoeppli phenomenon.3, 4 The fungal stain (hematoxylineosin) was positive and a portion of the biopsy specimen was inoculated onto freshly prepared Sabouraud-dextrose and mycologic agar with chloramphenicol and cycloheximide. However, the organism could not be grown from this specimen. Amphotericin B therapy was started and the dose was gradually increased to 1 mg/kg/day. The child underwent left frontal-temporal craniotomy, orbital deroofing and debulking of the hard intraorbital and facial mass. Specimens continued to be negative by culture. The patient's immunologic status showed a normal nitroblue tetrazolium test; serum immunoglobulin G was 1690 mg/dl (normal, 610 to 1570), IgA was 390 mg/dl (normal 50-200), T and B cells were of normal number and ratio and in vitro functional studies were normal. Postoperatively the child did well. However, his cheek mass increased in size. Liposomal amphotericin B was started on the 14th day after admission and the dose was increased to 5 mg/kg/day. There was no response to this regimen in which a total of 2484 mg of amphotericin B was given. Therefore itraconazole at 300 mg/day was added on the 28th day but without significant improvement. The child then lost vision in his left eye. Liposomal amphotericin B and itraconazole were discontinued on the 44th day and the child was given intravenous miconazole 30 mg/kg/day divided into 4 doses given every 6 h. He underwent enucleation of the left orbit and excision of the left cheek fungal infection, with resection of the left cervical lymph node. Pathologic examination of the left orbital lesion, left eyelid (upper and lower) and left cervical lymph node revealed granulomas and fungal hyphae similar to those found in previous biopsies. Mycologic studies from left orbital tissue identified a rapidly growing entomophthora species consistent with C. incongruus. Postoperatively he developed a swelling at the base of the nose. There was a palpable nontender mass with similar characteristics to the previously resected mass. The mass was palpable at the left side of the face near the site of surgical incision and crossed over the nasal bridge to the right side of the face, stopping at the medial canthi of the right eye. A computerized tomography scan of the orbits confirmed the previous finding. There was no intraorbital, intracranial or intranasal extension. No bony destruction was seen and the operative field on the left facial site showed no signs of relapse. A biopsy of the mass was performed and pathologic examination revealed fungal hyphae with features similar to findings in previous biopsies. A treatment protocol was formulated on the 50th day consisting of hyperbaric oxygen treatment twice daily, trimethoprim-sulfamethoxazole (trimethoprim 20 mg/kg iv every 6 h) in addition to the miconazole therapy. The hyperbaric oxygen treatments were given to 2 atmospheres of pressure while the patient breathed 100% O2. After 18 days of this regimen, including a total of 49 h of hyperbaric O2 therapy, the subcutaneous mass over the nose and the face totally regressed; these clinical findings were confirmed by computerized tomography scan. He was discharged home in good condition without medication. He was seen 2, 4 and 6 months after discharge, at which time he was gaining weight, and his physical examination and radiologic investigation showed no evidence of relapse. Mycologic studies. A portion of left orbital tissue examined under the microscope with a 10% KOH/methylene blue solution showed rare “skeleton-like” segmented hyphal elements. The specimen was cultured on Sabouraud-dextrose and mycobiotic agars at 30°C and brain-heart infusion agar with 5% sheep's blood at 37°C. Growth was evident overnight and was enhanced at 37°C. Forcibly discharged spores soon covered the Petri dish lid with a fine buffy down. Lactophenol aniline blue mounts from this and the enlarging colony revealed globose conidia with short protruding hyphal segments. Continued incubation showed spherical conidia with prominent basal papillae along with zygospore formation (Fig. 2) but no villose conidia (spores with hairlike appendages), structures characteristic of C. incongruus rather than the more commonly isolated Conidiobolus coronatus. Literature review and discussion. Entomophthoramycosis includes two distinct histologically similar, but clinically and mycologically distinct, entities: basidiobolomycosis and conidiobolomycosis.1, 2 Although the broad term zygomycosis has been advocated for these diseases, many experts prefer to use the name “entomophthoramycosis” because they are clinically and histopathologically distinct from the diseases caused by the Mucorales of the Zygomycetes. Unlike Basidiobolus, Conidiobolus largely afflicts adults. According to Clark 5 60% of patients with Conidiobolus disease are between 20 and 29 years of age. The remaining patients are almost all older adults; the disease is rare in children. No underlying disease or occupational factors are known.3 Conidiobolomycosis of the face is usually caused by C. coronatus. On the other hand C. incongruus has been isolated, to our knowledge, in only three cases reported in the literature. All cases involved deep structures. The first reported case was in a child and the other cases were adults. The pediatric patient with C. incongruus disease was reported by Gilbert et al.6 in 1970, studied by Eckert et al.4 in 1972 and correctly identified in 1976 by King and Jong.7 The child was a 15-month-old male with indolent pneumonia, mediastinitis and pericarditis. Cardiac catheterization with a pulmonary arteriogram suggested obstruction of the pulmonary venous flow. Exploratory thoracotomy showed a hard mass in the posterior mediastinum invading lung and pericardium over the left atrium and ventricle. Histologic examination of biopsy material from the hard mass was compatible with Entomophthora. C. incongruus was isolated in culture. The child responded to amphotericin B therapy. Of the two adult patients one was a 32-year-old woman with lymphocytic lymphoma complicated by leukemic transformation who presented with pneumonia which rapidly spread to the pericardium and heart. Despite therapy with amphotericin B and flucytosine, she died.8 The other patient was a 20-year-old woman who presented with a fever of 2 months duration, profound weight loss, hemoptysis and a subcutaneous mass in the left breast. Although the subcutaneous lesion improved with trimethoprim-sulfamethoxazole therapy, she had massive hemoptysis and died. At autopsy it was found that the infection involved the mediastinum, mucosa of the esophagus, bronchi, liver and jejunum. The patient reported in this case is the first orbitofascial infection caused by C. incongruus. The source of infection in our patient was probably the soil on which he fell; the fungus gained entrance from contaminated material inoculated directly into the orbit through the traumatized lid mucosa and then spread directly to deeper adjacent tissues. Conidiobolus species is found worldwide in soil, decaying vegetation, insects and the gastrointestinal contents of lizards and toads. It appears to be more abundant in warm climates. Routine laboratory tests during infection are not specific. Radiologic studies, as were used in this case, are helpful in delineating the extent of the disease. No serologic tests are available for diagnosis. Mass biopsies and tissue cultures are the preferred procedures for diagnosis, although the organism may be difficult to grow from tissue, as was noted in this case. The histopathologic features in our patient were consistent with entomophthoraceous infection. The Entomophthorales have broad, nonseptate or sparsely septate hyphae. There is no standard treatment for all forms of this disease. There have been suggestions that trimethoprim-sulfamethoxazole, amphotericin B and fluconazole are useful in the treatment of C. incongruus infection.3, 4, 7 Clinical failure has been reported during treatment with amphotericin B and flucytosine.3, 8 Our patient failed to respond to amphotericin B, including large dosages with the liposomal formulation, and to the addition of itraconazole. Yangco et al.9 suggest that imidazole derivatives such as ketoconazole or miconazole may be effective based on in vitro susceptibility testing. Surgical resection of infected tissue has brought temporary relief at best. Hyperbaric oxygen was used as adjunctive treatment in an adult with C. coronatus infection occuring in the maxillofacial region10 and has been used in rhinocerebral mucormycosis.11, 12 Inclusion of hyperbaric oxygen was founded on the premise that increasing the amount of oxygen dissolved in the plasma and adjacent tissues reduces tissue acidosis and retards fungal growth. In addition high partial pressures of 100% oxygen inhibits fungal growth in vitro.10, 13, 14 In our experience the use of hyperbaric oxygen has also played an important role in muscle flap survival and wound healing; this observation was documented in a recent publication.15 In our patient the combined treatment regimen consisting of hyperbaric oxygen, miconazole, trimethoprim-sulfamethoxazole and surgical resection and reconstruction with free myocutaneous flap was designed because of the progression of the illness and uncertain prognosis. We found rapid clearing of infection, which we believe has been cured. Although the importance of each treatment modality is uncertain, we believe that this combined treatment regimen should be considered in invasive Conidiobolus infections. Acknowledgments. We acknowledge the contribution of Dr. Gerald P. Bodey for his advice and interest in this patient. Sami Al-Hajjar, M.D., F.R.C.P.C., F.A.A.P.; John Perfect, M.D.; Fuad Hashem, M.B.B.S., F.R.A.C.S.(C); Haysam Tufenkeji, M.D., F.A.A.P.; Susan Kayes, S.M.(ASCP) Departments of Pediatrics (SAH, HT), Surgery (FH) and Pathology and Laboratory; Medicine (SK) King Faisal Specialist Hospital and Research Center; Riyadh, Saudi Arabia; Department of Medicine; Duke Medical Center; Durham, NC (JP)FIG. 1: The Splendore-Hoeppli phenomenon.FIG. 2: C. incongruus sporulation: zygospores.