Entomophthroramycosis

ENTOMOPHTHORAMYCOSIS
Abhijit Chaudhury

TAXONOMICAL CONSIDERATIONS
• Originally, fungi were part of the Plant
Kingdom (Plantae), and subdivision
Thallophyta.
• Three classes were recognised:
Phycomycetes, Ascomycetes, Basidiomycetes
(based on the morphologic similarities of
sexual reproductive structures), and
Deuteromycetes (Asexual reproduction).

• In 1969, Whittaker created the Kingdom
Fungi.[Whittaker RH. New concepts of kingdoms of organisms. Evolutionary relations are
better represented by new classifications than by the traditional two kingdoms. Science 1969;
163:150–60].
• The agents causing mucormycosis,
entomophthoramycosis,and other fungi that
produce coenocytic (aseptate) vegetative hyphae
and sexual spores called ‘‘zygospores’’ or
‘‘oospores’’ were classified in the Phycomycetes
group. [Emmons CW, Binford CH, Utz JP, Kwon-Chung KJ. Medical
mycology.3rd ed. Philadelphia: Lea & Febiger, 1977:254–84].

• Because Phycomycetes comprised a
miscellaneous assemblage of evolutionarily
unrelated organisms, the class Phycomycetes was
abolished [Whittaker, 1969], and the members of
Phycomycetes were accommodated in a series of
classes: Zygomycetes, Chytridiomycetes,
Hypochytridiomycetes, Trichomycetes, and
Oomycetes [Ainsworth GC. Introduction and keys to higher taxa. In:
Ainsworth GC, Sparrow FK, Sussman AS, eds. The fungi. IVA. A taxonomic
review with keys. New York: Academic Press, 1973:1–7].

• Further classification of the fungal kingdom on
the basis of shared, derived characters delimited
the kingdom to include only Chytridiomycota,
Zygomycota, Ascomycota, and Basidiomycota,
and this classification scheme has been
universally accepted until a decade ago.
• The phylum Zygomycota contained Mucorales,
Entomophthorales, and 8 other orders.

• Zygomycosis was originally described as a
convenient and inclusive name for 2
clinicopathologically different diseases:
Mucormycosis caused by members of
Mucorales and Entomophthoramycosis caused
by species in the order Entomophthorales of
Zygomycota.

• Zygomycota underwent major taxonomic
changes in 2007.
• Hibbet and others proposed to eliminate
Zygomycota and the taxa conventionally
placed in Zygomycota were distributed among
the phylum Glomeromycota and 4 subphyla of
uncertain placement.

• The Mucorales and Entomophthorales, which
contain zoopathogenic fungi, and 2 other
orders including Kickxellales and Zoopagales
were nraised to the rank of subphyla:
Mucoromycotina, Entomophthoromycotina,
Kickxellomycotina, and Zoopagomycotina.
(Hibbett DS, Binder M, Bischoff JF, et al. A higher-level phylogenetic
classification of the Fungi. Mycol Res 2007; 111:509–47).

Nomenclature of Disease
• Emmons proposed the name
‘‘phycomycoses’’ to provide a convenient and
an inclusive term for mycoses caused by any
one of the several species of Phycomycetes.
• ‘‘Phycomycosis’’ became widely accepted as a
convenient disease name, irrespective of its
diversity in clinical course and etiology .

• Clark, in 1968, however, supported use of the
term ‘‘mucormycosis’’ for the diseases caused
by species of Mucorales, to distinguish them
from ‘‘subcutaneous phycomycosis’’ caused by
fungi belonging to Entomophthorales.
• She also proposed the name
‘‘Entomophthoromycosis’’ for subcutaneous
phycomycosis. (Clark BM. The epidemiology of phycomycosis. In:
Wolstenholme GEW, Porter R, eds. Systemic mycoses. London: J & A Churchill,
1968:179–205)

• The names ‘‘mucormycosis’’ and
‘‘entomophthoramycosis’’ have been
embedded in the medical literature for .50
years, and the time has come to replace
‘‘zygomycosis’’ with these 2 names. [ Kwon-Chung
KJ. Taxonomy of Fungi Causing Mucormycosis and Entomophthoramycosis
(Zygomycosis) and Nomenclature of the Disease: Molecular Mycologic
Perspectives. Clinical Infectious Diseases 2012;54(S1):S8–15].

MUCORMYCOSIS
• Worldwide
• Produce numerous deciduous
asexual spores within the
sporangium (sporangiospores).
• Zygospores of Mucorales are
produced between2 opposed
suspensors originating from
different hyphae.
• Cause an acute angioinvasive
infection primarily in
immunocompromised
individuals.
• Absent
Entomophthoramycosis
• Tropical and subtropical
• Produce a single conidium (with
no sporangium) on each
conidiophore.
• Zygospores of Entomophthorales
are produced by the union of 2
contiguous cells of a hypha.
• Produce chronic and
subcutaneous infection mostly in
immunocompetent individuals.
• Thick eosinophilic sleeves
surround the fungal hyphae.

[ Kwon-Chung KJ. Taxonomy of Fungi Causing Mucormycosis and
Entomophthoramycosis (Zygomycosis) and Nomenclature of the Disease:
Molecular Mycologic Perspectives. Clinical Infectious Diseases
2012;54(S1):S8–15].

Historical Aspects
• The first well-documented case of disease
caused by members of Mucorales was
published in 1885 by the German pathologist
Paltauf.
• It was a systemic infection with gastric and
rhinocerebral involvement, which Paltauf
described as ‘‘Mycosis Mucorina’.
[Paltauf A. Mycosis mucorina: ein Beitrag zur Kenntnis der
menschilchen Fadenpiltzer-krankungen. Virchows Arch Pathol Anat
1885; 102:543–64].

Historical Aspects
• The disease name ‘‘mucormycosis’’ was
subsequently used by the American
pathologist R. D. Baker to denote a mycosis
caused by certain members of Mucorales.
[Baker RD. Mucormycosis, a new disease? JAMA 1957; 163:805–8].
• Entomophthoramycosis (Basidiobolomycosis)
was first reported in 3 Indonesian children in
1956. [Kian Joe L, Njo-Injo TE, Pohan A, Van der Muelen H,
Emmons CW. Basidiobolus ranarum as a cause of subcutaneous
phycomycosis in Indonesia. AMA Arch Dermatol 1956; 74:378–83].

Historical Aspects
• Cases were subsequently reported from
Brazil, India, Tropical Africa, SE Asian
Countries.
• Indian isolates were classified as B.
haptosporus. [Srinivasan M, Thirumalachar M. Basidiobolus species
pathogenic for man. Sabouraudia 1965.; 4: 32-34].
• Later, the consensus was that B.haptosprus is
identical to B. ranarum and the later name has
priority.

Historical Aspects
• The first human case of Conidiobolomycosis
was reported in 1965 in a patient from West
Indies. [Bras G et al. A case of phycomycosis observed in Jamaica. Am J
Trop Med Hyg 1965; 14: 141-145].
• Systemic Conidiobolomycosis was reported in
1970 (Pericarditis).
• Disseminated Conidiobolomycosis with death
was reported in 1984 caused by C. incongruus.

Human Aetiological Agents
• Basidiobolus ranarum
• Conidiobolus coronatus
• C. incongruus
• Conidiobolus lamprauges

Epidemiology: A. Basidiobolus
ranarum
• Reported mainly in tropical areas of Asia
(India, Indonesia, and Myanmar), Africa
(Uganda, Nigeria, Cameroon, Togo, Ivory
Coast, Sudan, Senegal, Somalia, and Kenya),
South America (mostly Brazil), North America
(Mexico), and recently Australia. [Kwon-Chung K.J.,
Bennett J.E.: Entomophthoramycosis. In Medical Mycology. Philadelphia:
Lea and Febiger, 1992].

ranarum
• The fungus occurs in decaying vegetation, soil,
and as a saprobe in the intestinal contents of
various insectivorous reptiles (lizards,
chameleon), amphibians (toads), and mammals
(bats, kangaroos, and wallabies)[Kafor J.I., Testrake D.,
Mushinsky H.R.,et al. A Basidiobolus sp. and its association with reptiles and
amphibians in Southern Florida . Sabouraudia: J Med Vet Mycol 1984; 22: 47]
• Infections caused by Basidiobolus ranarum are
mainly diagnosed in children (80% under the age
of 20 years) with a male/female ratio of 3:1.

ranarum
• The portal of entry is believed to be the skin
after insect bites, scratches, and minor cuts.
This helps to explain the most common
presentation in young children involving the
thighs and buttocks. However, there is rarely a
history of previous trauma.
[Elias J. Anaissie, Michael R. McGinnis, and Michael A. Pfaller Eds. Clinical
Mycology ,2009; 2nd Ed. Chapter 12, 297-307; Elsevier]

Epidemiology: B. Conidiobolus
coronatus
• Conidiobolus coronatus infections have been
reported from tropical portions of Africa
(mostly Cameroon and Nigeria, but also chad,
Zaire, Kenya, Central African Republic, Guinea)
and the Americas (Costa Rica, Caribbean
islands, Columbia, Brazil). [Drouhet E., Ravisse P.:
Entomophthoromycosis. In Borgers M., Hay R., Rinaldi M.G.(eds) Current
Topics in Medical Mycology. Barcelona, Spain: J.R. Prous, 1993]

coronatus
• The fungus is found in decaying wood, plant
detritus, on insects, and in the gastrointestinal
tract of lizards and toads.
• There are seasonal variations in the yield of C.
coronatus from soil, a maximum being
recorded in September and October, which
suggests an influence of climate on spore
survival, which may also help explain the
geographic distribution of the infection. [Kwon
Chung and Bennett, 1992]

coronatus
• There is a male/female ratio of 10:1 and a
predominance of the disease among young
adults. Infection is rare among children. There
is no known underlying predisposing factor for
the infection. [Drouhet E., Ravisse P, 1993.]
• The spores are believed to enter the body by
inhalation and then invade tissues through
wounded nasal mucosa.

Clinical Manifestations
• Clinical entities are chronic, often indolent,
and not life-threatening infections except in
anecdotal cases of disseminated infections.
• Histologic features are identical, but clinical
features differ.

Clinical Manifestations:
Basidiobolomycosis
• Most cases seen in children.
• The presenting feature is a single painless,
unilateral, well-circumscribed subcutaneous
mass that usually affects the buttock or the
thigh but can also be seen in the arm, the
neck, the face or the trunk.
• The disease starts as a single nodule that
progressively grows. The swelling is often
described as woody and hard.

Basidiobolomycosis
• There is no ulceration and the mass is not adherent to
deeper tissues, although involvement of muscle had
been described.
• Enlargement of local lymph nodes is sometimes seen,
with the fungus sometimes being cultured from the
corresponding biopsy specimens.
• The lack of draining sinuses, the absence of adherence
to underlying structures, and the lack of extension to
bone make the differential diagnosis with mycetoma
easy.
• Unusual localization includes gastrointestinal infection.

Conidiobolomycosis
• The infection starts in the nasal mucosa and
progressively extends to adjacent areas
bilaterally, including the nose, cheeks, upper
lip, paranasal tissues, and pharynx.
• The edema affecting all the infected areas
leads to significant distortion of the face.
• Apart from obvious changes in appearance,
the patient may complain of nasal
obstruction, rhinorrhea, and epistaxis.

Conidiobolomycosis
• Invasion of the pharynx may cause dysphagia.
• The lesion does not usually involve the bones
• The evolution of the infection is slow over years.
• There is no tendency for the mass to ulcerate or
become verrucous.
• The mass is usually anchored to the dermis.
• There is usually no fever and no biologic signs of
infection. Blood cell count and chemistry are
normal

Conidiobolomycosis
• Three cases of infections due to C. incongruus have
been described so far.
• One occurred in an immunocompromised patient, in
whom the initial pulmonary infection was rapidly fatal
after spreading to the pericardium and heart.
• The two other cases occurred in a 15-month-old boy
and a 20-year-old woman with no underlying disease.
• The infection initially involved the lungs and
mediastinum with dissemination to adjacent tissues
and eventually caused death of the young woman from
massive hemoptysis; but the boy survived.

THERAPY
• Surgery: Surgical resection alone is not
effective in managing infections caused by
Basidiobolus or Conidiobolus spp. Cosmetic
surgery can be proposed after prolonged
antifungal therapy and sterilization of the
lesion.

ANTIFUNGAL THERAPY
• Treatment is not well defined for
entomophthoraceous fungi.
• Saturated potassium iodide (30 mg/kg/day)
has long been the treatment of choice for
chronic infections caused by Basidiobolus and
Conidiobolus [Kwon-Chung and Bennett 1992, Drouhet and
Revisse 1993].

ANTIFUNGAL THERAPY
• Since the discovery of azoles, patients have
improved with, if not been cured by,
ketoconazole or itraconazole.
• The efficacy of fluconazole ranges from complete
cure,to partial improvement or failure.
• Amphotericin B is rarely prescribed for chronic
infections [Fournier S., Dupont B., Begue P.,et al. Infection rhino-
faciale Conidiobolus coronatus avec lyse osseuse et adenomegalie.
Difficultes therapeutiques . J Mycol Med 1995; 5: 35]

LABORATORY DIAGNOSIS AND
MYCOLOGICAL ASPECTS
A. DIRECT EXAMINATION:
 Punch biopsy material/ scrapings of nasal
mucosa mounted in KOH.
 Broad, non-septate or sparsely septate
hyphae with refractile walls and granular
inclusions may be seen.

B. Histopathology
• Chronic inflammatory process can be seen with small
abscesses surrounded by a granulomatous tissue
reaction.
• A strong eosinophilic perihyphal reaction is often
observed (Splendore–Hoeppli phenomenon) that is
variable in size (2–6 μm). [Rippon J.W.: Zygomycosis. In Rippon
J.W.(eds) Medical Mycology. The Pathogenic Fungi and the Pathogenic
Actinomycetes. Philadelphia: WB Saunders, 1988]
• Broad irregular hyphae (4–30 μm) with thin walls and
rare septation can be seen, singly or in clusters.
• There is no invasion of blood vessels or infarction of
tissue,

Entomophthoromycosis caused by "Conidiobolus coronatus" -
Haematoxylin and eosin (H&E) stained section of tissue showing broad
sparsely septate hyphae surrounded by an eosinophilic sheath
(Splenodore-Hoeppli phenomenon) typical of
Entomophthoromycosis. (Courtesy Dr R. Garrison, V.A. Medical Centre,
Kansas City, U.S.A.).

C. CULTURE
• Scrapings from nasal mucosa, biopsy material from the
polyps, or material from skin biopsy are used as
specimen.
• Biopsy specimen should be cultured immediately as
B.ranarum dies quickly in tissues kept in a refrigerator.
• Tissue biopsy should be minced and not homogenized.
Homogenization in a tissue grinder should be avoided,
because it decreases culture yield by destroying
hyphae.
• SDA with antibiotics can be used. Cycloheximide
should not be used in SDA.
• Incubation at 250-300 C for 2-5 days.

Basidiobolus ranarum: Culture
Characters and Morphology
• Colonies are yellowish to gray; thin, flat,
glabrous, and waxy with many radial folds.
• The hyphae are wide (8-20µm) with
occasional septa in young cultures, but
become increasingly septate as sporulation
proceeds.
• Sporulation become evident within 10 days
with development of zygospores.

• Zygospores are smooth walled and are
formed after the conjugation of two adjacent
hyphal cells.
• A prominent beak is found attached to one
side which is the remnant of conjugation tube.
• Conidia are formed when the apical portion
of the conidiophore has enlarged and the
globose conidium is blown out from the tip of
this swelling.

• The swollen part becomes the subconidial
vesicle.
• It also produces passively detached,elongate,
adhesive conidia.
• Meristospore: The cytoplasm of some conidia
cleaves into sporangiospores.
• A medium containing casein hydrolysate, low
glucose, and glucosamine enhances
sporulation.

p: primary conidia are forcibly discharged, with the remnant wall of
ruptured conidiophores,
s: secondary conidia, and a: ellongate conidia with an apical adhesive
knob(capilliconidia) produced from a thin hypha.

(A, B, and C) Sporangiospores of B. ranarum showing cleavage formation to produce
meristospores (black arrow), knob-like adhesive tip (white arrow), and ballistospores with
hyphal tag (white arrowhead). D) Thick-walled zygospores. (E) A zygospore with a beak.
Khan Z U et al. J. Clin. Microbiol. 2001;39:2360-2363

Conidiobolus coronatus: Culture
• Rapidly growing colony.
• Creamy, glabrous, and waxy at first ; becomes
powdery when short, white aerial hyphae
develop.
• Vegetative hyphae are frequently septate.
• With age, colour of colony becomes buffy.
• The inner side of plate or tube is covered by
white powdery material (forcibly discharged
spores).

• Conidiophores: 12-18x60-90 µm size originate
from engorged hyphal segments.
• Conidiophores are phototrophic, and
discharge conidia towards light source.
• Conidia are multinucleate, and globose with
conspicuous basal papilla, which marks the
former point of attachment to the
conidiophore.

• The conidiophore releases the primary
conidia up to 4 cm into the air using the
evertion mechanism which is the
characteristic feature of the Conidiobolus
genus.
• The conidia also produces multiple, short,
hair-like appendages called villi, which
separates C.coronatus from C. incongruus.

Conidiobolus incongruus: Culture
• Colony similar to C.coronatus
• Yellowish zygospores
• No villous conidia
• Primary conidia have sharply pointed papilla.

(A) CT scan of the midface: signs of sinusitis (*) and osteolyses of the medial part of the right orbit(→ (B) Hyphae with orthogonal
branches in periodic acid-Schiff staining (magnification, ×600) in the biopsy specimens of the ethmoidal cells. (C to E) Micromorphology
of Conidiobolus incongruus (lactophenol blue; magnification, ×1,000). (C and D) Wide vegetative mycelium with moderate septation. (D
and E) Large single-celled primary conidia with pointed papillae. (F) Septate hyphae with orthogonal branches in the calcofluor white
staining from the biopsy specimens of the right eye (postmortem; magnification, ×400). (G) Perivascular accumulation of fungal hyphae,
with infiltration of the vessel wall and beginning infiltration of surrounding brain tissue in the frontal cortex (Grocott stain; magnification,
×200).

Entomophthroramycosis

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