Case of the Month - SASPID

March 2022


Prof NM du Plessis

Dr M Verster (Paediatrician, Cintocare hospital, Pretoria)

Case presentation

JM, a previously healthy 8-year-old boy, was admitted in late-April 2021 with a necrotic lesion invading his right orbit.

His symptoms started in October 2020. After a swimming lesson, his parents noted a small black lesion under his right eye (just underneath the area that the swimming goggles would normally cover). They assumed that he injured his face in the swimming pool. The lesion did not resolve, and grew larger over a period of 1 month. They did not report any fever or weight loss at the time. Nasal congestion was reported intermittently during this period.

A skin biopsy was done in November 2020, and repeated in January 2021. The biopsies showed a vaguely granulomatous inflammatory process.

Differential diagnosis

The differential diagnosis of an invasion granulomatous skin lesion can include a number of etiologies:(1)

GPA = granulomatosis with polyangiitis, LCH = Langerhans cell histiocytosis, SLE = systemic lupus erythematosus.

Master JM was started on oral Fluconazole and Co-amoxiclav, but the lesion grew aggressively and started involving his right orbit. He also developed significant submandibular and cervical lymphadenopathy. He was subsequently referred to an oncologist for further management. Chemotherapy treatment for suspected Langerhans Cell Histiocytosis (although immunophenotyping remained inconclusive) was initiated by the oncologist, but without clinical improvement. At the time of his referral, he had complete destruction of the right orbit with loss of vision in his right eye (Figures 1-3 show the progression of the lesion).

Figures 1-3: The pictures illustrate the progression of the lesion under the right eye (from left to right) (Written permission given by the parents)


The following laboratory tests were performed

Test performed

Reference ranges



11.5 – 15.5 g/dL



0.35 – 0.45 L/L



150 – 450 x 10^9/L


Leucocyte Count

5.0 – 15.0 x 10^9/L



1.5 – 8.0 x 10^9/L

51.0% 2.95


1.5 - 7.0 x 10^9/L

37.0% 2.14


< 4.1 mg/L


Figures 4&5: MRI brain and orbits pre-surgery (Written permission given by the parents)

There is a heterogeneous intermediate signal intensity lesion demonstrated in the right orbit.

The lesion extends from the infraorbital area, at the level of the mandible. Medial extension deforms and displaces the right nostril. There is lateral extension to the zygomatic arch. Further superior extension of the lesion is noted into both the intra- and extraconal spaces of the orbit. 

Review of the previous biopsies showed the presence of numerous fungal elements.

Further management

C. gattii is a basidiomycetous fungus found in the environment. In the current HIV-pandemic, C. neoformans has been regarded as the more prevalent fungal infection causing cryptococcosis. This case gives us the opportunity to gain knowledge regarding the difference in presentation and management of the less common C. gattii, an important emerging fungal pathogen that also affects immunocompetent individuals. There are limited data available regarding the incidence of C. gattii in South Africa as well as the incidence in the HIV infected compared to the HIV uninfected population. One South African study in Gauteng that looked at cryptococcal infection during the 2002-2004 period, reported that only 2.4% of cases of cryptococcal meningoencephalitis could be ascribed to C. gattii.  Of these patients, the majority (61%) was found to be HIV infected, 37% had unknown HIV status compared to 2.2% that was confirmed HIV negative (Morgan et al). Another South African study that observed cryptococcal infections in the paediatric population found that children were significantly more likely than adults to be infected with C. gattii, 9 vs. 3% (Meiring et al). Important to note however, is the prevalence of C. gattii might be higher than currently estimated since the laboratory diagnosis of C. gattii can be challenging (See laboratory aspects of Cryptococcus identification, below).

What is the natural reservoir of C. gattii? 

Urgent surgical debridement and biopsies were done shortly after admission. JM required extensive surgery to remove the necrotic tissue and his right orbit was not salvageable.

The fungus was confirmed to be of the Rhizopus species, causing rhinocerebral mucormycosis. Fungal elements were subsequently also identified in the right orbit and in the bony region of the maxillary sinus:

Final diagnosis

Cutaneous mucormycosis, likely Rhizopus species, with orbital invasion and destruction

Further work up did not identify a clear underlying cause for his invasive fungal infection:

  • Immune work up did not identify any underlying primary immunodeficiency
  • HIV ELISA was negative
  • No evidence of diabetes mellitus

High dose intravenous Amphotericin B was continued for 8 weeks, followed by a 6-month course of oral posaconazole.

JM has recovered and has gone back to school. The vision in his left eye remains unaffected.



Mucormycosis is an angioinvasive fungal infection, due to fungi of the order Mucorales. These molds live throughout the environment. The prevalence of mucormycosis in India is about 80 times the prevalence in developed countries, being approximately 0.14 cases per 1000 population. (2) Cutaneous mucormycosis is the third most common clinical type of mucormycosis. The signs and symptoms vary widely, and it is important to make the diagnosis as early as possible in order to achieve a better outcome.

The most common risk factors/predisposing conditions include:

  • diabetes mellitus (DM), with or without ketoacidosis
  • hematological malignancies (HM)
  • other malignancies
  • transplantation
  • prolonged neutropenia
  • corticosteroids
  • trauma
  • iron overload
  • illicit intravenous drug use
  • neonatal prematurity
  • malnourishment  
  • Immunocompetent patients can also be affected, when the spores of the fungus are directly inoculated in the skin, as a result of trauma or burns. (2)
  • In addition, new risk factors are reported from Asia, including post-pulmonary tuberculosis and chronic kidney disease.

Increasing cases of rhino-orbital mucormycosis in people with COVID-19 were recently reported, especially from India. Diabetes was present in 80% of cases, while corticosteroid treatment was given for COVID-19 in 76.3% cases. (3)

Clinical features – important differentiating principles

Due to the histological evidence of a “vaguely granulomatous inflammatory process”, the initial diagnosis of Langerhans cell histiocytosis was made. Langerhans cell histiocytosis (LCH) is a rare clonal disease of the monocyte-macrophage system characterized by uncontrolled proliferation and accumulation of CD1a+/CD207+ dendritic cells (DCs) as a result of continuous immune stimulation. Langerhans cell histiocytosis can occur at any age. However, peak occurrence occurs between 1 and 4 years of age.  The diagnosis of LCH is based on histological criteria established by the Histiocyte Society in 1987. To make a diagnosis, it is necessary to perform a histological examination with immunophenotyping. The most frequent presenting signs and symptoms of LCH include painful bone lesions and rash. Often non-specific symptoms become prominent, such as fever, poor appetite, weight loss, fatigue, irritability and changes in behaviour.  In the youngest children, the disease is often an multisystem disease with fever and symptoms of failure in various organs. In a Japanese study, the patients with skin lesions were younger than those with bone lesions. In a previous French study, 77% of the patients with the skin lesion were less than 1 year old. Sometimes there are superficial ulcerations of the lesions accompanied by oozing as the result of secondary processes leading to a bacterial superinfection. Ulcerative lesions behind the ears or involving the scalp, axillae, genitalia, or perianal region are often misdiagnosed as bacterial or fungal infections.

Key learning points to diagnosis and therapeutic approaches in this case study

  1. Invasion granulomatous skin lesions have a broad differential diagnosis, and can be life threatening if not diagnosed and treated early. A careful history, including trauma and predisposing risk factors, should be taken in all patients presenting with a rapidly enlarging skin lesion.
  2. Adequate biopsies, including fresh specimens for bacterial and fungal culture, is imperative to make the correct diagnosis. Histopathology is a very important diagnostic tool since it distinguishes the presence of the fungus as a pathogen in the specimen from a culture contaminant and is indispensable to define whether there is blood vessel invasion. Routine hematoxylin and eosin (H&E) stains may show only the cell wall with no structures inside, or occasionally, very degenerate hyphae. Stains that can help highlight the fungal wall include Grocott methenamine-silver (GMS) and periodic acid-Schiff PAS stains, although PAS gives a better visualization of the surrounding tissue compared to GMS. For a rapid presumptive diagnosis of mucormycosis direct microscopy of KOH wet mounts can be used. It can be applied to all materials sent to the clinical laboratory, preferably using fluorescent brighteners such as Blankophor and Calcofluor White together with KOH, which enhance the visualization of the characteristic fungal hyphae, in this case requiring a fluorescent microscope. Direct microscopy of fresh material is an inexpensive, yet invaluable method to rapidly give a presumptive diagnosis and to define clear surgical margins for invasive fungal infection intraoperatively, and it is strongly recommended, along with histopathology, by a panel of experts of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium (ECMM/MSG ERC). These methods, however, are not able to identify a fungus to the genus or species level. Another method, immunohistochemistry using monoclonal antibodies against R. arrhizus (recently commercially available) can aid in the diagnosis when cultures are negative and has been proven useful for differentiating aspergillosis from mucormycosis (sensitivity 100%, specificity 100% for mucormycosis) and has gained a moderate recommendation of B IIu in the recent ECMM/MSG ERC guidelines. Culture of specimens is essential for the diagnosis of mucormycosis since it allows identification to the genus and species level, and eventually antifungal susceptibility testing. Most medically important Mucorales are thermotolerant and are able to grow rapidly at temperatures of 37 °C. They grow on virtually any carbohydrate substrate, colonies appearing usually within 24–48 h and identification is based on colonial and microscopic morphology and growth temperature. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) identification of cultured Mucorales is a promising method for those laboratories that are accordingly equipped, but the commercially available databases should be expanded further, and more validation data are needed. Until then, molecular identification remains the gold standard. (4)
  3. Invasive fungal infections such as mucormycosis need urgent surgical debridement together with aggressive antifungal therapy. Mucormycosis-associated 90-day mortality remains high despite the advent of newer antifungals. First-line antifungals with good efficacy and safety remain an urgent unmet need. Owing to its broad-spectrum antifungal activity, traditionally amphotericin B formulations have been the antifungal of choice for the treatment of mucormycosis. However, with the advent of newer triazoles, specifically posaconazole and isavuconazole, clinicians now have access to a wider range of therapeutic options. Intravenous lipid-based Ampho B does not confer a survival advantage over intravenous C-AmB but was associated with fewer adverse effects. Initial combination antifungal therapy is not associated with reduced mortality compared with initial AmB monotherapy, but requires further investigation. Surgery is fundamental to improving survival and must be accessible to all patients.(5)


  1. Granulomatous Disease in the Head and Neck: Developing a Differential Diagnosis | RadioGraphics [Internet]. [cited 2022 Mar 4]. Available from: https://pubs.rsna.org/doi/10.1148/rg.345130068
  2. Global Cutaneous Mucormycosis: A Systematic Review - ProQuest [Internet]. [cited 2022 Mar 4]. Available from: https://www.proquest.com/docview/2632816614?accountid=14717
  3. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India - ScienceDirect [Internet]. [cited 2022 Mar 4]. Available from: https://www-sciencedirect-com.uplib.idm.oclc.org/science/article/pii/S1871402121001570
  4. Epidemiology and Diagnosis of Mucormycosis: An Update [Internet]. [cited 2022 Mar 4]. Available from: https://www.mdpi.com/2309-608X/6/4/265
  5. Contemporary management and clinical outcomes of mucormycosis: A systematic review and meta-analysis of case reports - ClinicalKey [Internet]. [cited 2022 Mar 4]. Available from: https://www-clinicalkey-com.uplib.idm.oclc.org/#!/content/playContent/1-s2.0-S0924857919300020?retur...

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