In April 2012, a 54-year-old male patient presented to the outpatient department of the "Centre de Recherche Medicale de la Ngounie," Fougamou, Gabon. He complained of grotesque facial deformity (Fig 2), dysarthria, hypersalivation, and incapacity to eat properly.
In July 2009, he had a persisting rhinitis and recurrent epistaxis, while he was still working as a gardener. Six months later, a nodule occurred on his right nostril. Within three months, the nodule spread to the nasal bridge, causing reddish and hyperthermic swellings.
Physical examination revealed ligneous hard swellings of the whole face and left part of the neck. The upper and lower eyelids of both eyes were swollen, impairing his vision. No ulcerations of the skin or mucosa and no enlarged lymph nodes were noticed.
Laboratory analyses revealed an anaemia (haemoglobin 8.1 g/dl) and an absolute (2290/mm3) and relative (29%) eosinophilia, no leucocytosis. Microfilaria of Loa Loa were detected in venous EDTA blood (Citrate-Saponin acid method) and stool samples revealed an infection with Ascaris lumbricoides and Trichuris trichiura. We found no serologic evidence for hepatitis A, hepatitis B, syphilis, or HIV infection.
A rhinoentomophthoromycosis was suspected and a biopsy was taken (buccal region, 1 cm3) including the skin and indurated subcutaneous tissue. Histopathology revealed fungal hyphae suggestive for Conidiobolus sp. (Fig 3A, 3C and 3D) and the Splendore-Hoeppli phenomenon (Fig 3B). The histopathology did not show any evidence for tuberculosis, leprosy, or any malignancy. Fungal cultures showed no growth. DNA from clinical samples was extracted and amplified using fungus-specific primers. A BLAST search using the sequence of the 676bp amplicon yielded a 100% match with sequences of C. coronatus (HQ602777.1, AJ345094.1, and AY997041.1).
Antifungal therapy (fluconazole 400 mg, terbinafine 250 mg, SID, po) was started in April 2012. After partial response during the first nine months of treatment, no further reductions were seen in the following three months. Dosages were therefore increased (to fluconazole 800mg, terbinafine 500mg, SID, po) and given for further six months. We observed no further improvement and stopped the treatment in September 2013 after 18 months in total. Helminth infections were treated with albendazole 400 mg (day 1, 3, and 9, po). Ferrous glycine sulfate (100 mg, BDS, po) was given for one month, and the haemoglobin level normalized (haemoglobin 13.7 g/dl). Serum transaminases (ASAT, ALAT) and creatinine were controlled every 30 days to monitor potential side effects. The laboratory parameters stayed within normal limits. Residual swellings remained after treatment. The patient is free of relapse after 14 months without antifungal therapy (Fig 2D).
Where possible, we considered the recommended items proposed by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group.
Literature search was performed on January 13, 2013, and included literature published until December 31, 2013. An update was performed on January 18, 2015, to add all articles published between January 1 and December 31, 2014, plus the case that we reported here.
We assessed the literature using the medpilot portal (www.medpilot.de), which accesses several electronic databases, including Current Contents, Catalogue of the U.S. National Library of Medicine (NLM), and MEDLINE (see website for complete list of databases). Search terms were "phycomycosis," "zygomycosis," "entomophthoromycosis," "entomophthora," "conidiobolus," "basidiobolus," "conidiobolomycosis," "basidiobolomycosis," "facial swelling," and "rhinoentomophthoromycosis" (S1 Table). Titles and abstracts were screened for eligibility criteria. All cases that were diagnosed by the authors of the papers as an infection of nasopharyngeal and/or facial structures due to entomophthorales were eligible. The case definition included (i) rhinitis and/or intermittent epistaxis and/or sinus pain and/or tissue augmentation of nasopharyngeal and/or facial structures and (ii) confirmation of an entomophthoralean fungi infection by histopathology, culture, or PCR.
The reference lists of all eligible articles were screened for additional articles that were not detected using the search terms. All manuscripts were fully reviewed for initial symptoms, course of the disease, diagnostic tools, therapy, and outcome.
All eligible cases were reviewed for year of publication, country, continent, climate zone, age, sex, duration of disease before diagnosis, symptoms (i.e., coryza, epistaxis, nasal obstruction, facial elephantiasis), tissue invasion (i.e., nasal mucosa, nasal bridge, cheek, upper and lower lip, eyelids, orbit, lymph nodes, viscera), diagnostics for confirmation (i.e., smear microscopy, culture, histology, presence of the Splendore-Hoeppli phenomenon), antifungal treatment (i.e., agent, duration of therapy), and outcome (i.e., residual swellings, cure, sequelae, or death during follow-up). Cure was defined as being disease free after treatment with complete resolution of all clinical symptoms. Residual swellings were considered when the patients were disease free after treatment but showed persisting tissue augmentation.
Cases were classified into atypical, early, intermediate, and late disease.
Atypical disease was defined as ulcerations of the skin and/or invasion of the orbit, central nervous system, visceral organs, bones, muscles, and/or lymph nodes within 11 months after onset of disease (Fig 4).
Patients with atypical disease were younger (Table 1), more frequently immunosuppressed (29% vs. 0%, p<0.001), and more commonly female (76% versus 23%, p = 0.001). They had active tuberculosis more often (29% versus 3%, p<0.001), originated more likely from non-tropical regions (43% versus 3.1%, p<0.001), and had more frequent infections with C. incongruus (43% versus 0.8%, p<0.001) compared to patients with typical rhinoentomophthoromycosis (early, intermediate, and late disease).
As atypical disease differs from early, intermediate, and late disease in several aspects, we assessed the homogeneity of patient's data only from early, intermediate, and late disease. These groups were comparable concerning age, distribution of all pathogens among the stages, and number of antifungal drugs (Table 1). Pooled data of early, intermediate, and late disease showed that duration of disease before diagnosis correlated inversely with cure (r = -0.34, p<0.001). Additionally, duration of disease before diagnosis correlated positively with residual swellings after treatment (r = 0.27, p = 0.02) and no response to treatment (r = 0.27, p = 0.03). Involvement of the lower lip (16%, n = 21) correlated negatively with cure (r = -0.34, p<0.001) and correlated positively with duration of disease before diagnosis (r = 0.38, p<0.001) and residual swellings after treatment (r = 0.32, p<0.001).