ZYGOMYCOSIS/MUCORMYCOSIS

PREPARED BY: SNEHA POUDEL

 INTRODUCTION
• Mucormycosis is an acute opportunistic infection caused by several fungi belonging to
phylum Glomeromycota.
• Mucormycosis is an umbrella term used for diseases caused by many non-septate
filamentous fungal species.
• Earlier classified under Orders Mucorales and Entomophthorales, they were
previously considered sub ordinate members of phylum Zygomycota and now are
elevated to the rank of sub-phylum Mucoromycotina.
• They have predilection to invade blood vessels being angioinvasive in nature thereby
leading to extensive necrosis of the surrounding area and forming embolism.
 GENERAL CHARACTERISTICS
• The mucormycetes is a group of lower fungi and their hyphae are generally non-
septate, sparsely septate or pauci-septate.(having few internal crosswalls)
• However, when these septa occur they have solid cross-walls with no pores and there
is no flow of cytoplasmic material between cells.
• These reproduce asexually by way of sporangiospores formed within a sac called a
sporangium and/or by means of conidial development.
• These fungi also reproduce sexually by formation of a single, dark, thick-walled spore
called zygospore.
• The sub-phylum Mucoromycotina contains the order Mucorales, which is the most
clinically important and includes the genera Lichtheimia (formerly Absidia), Mucor,
Rhizomucor and Rhizopus species.
 EPIDEMIOLOGY
• All clinical forms of mucormycosis occur following infection by fungi, which are
found as saprotrophic in the environment and on a wide range of substrates including
soil.
• Their spores are widely distributed, growing on leaf litter and other decaying
carbohydrate substrates.
• These are not as abundant in free air but can be found in large number in damp
interiors and around composing vegetation.
• It is even present as ‘bread molds’ appearing as grayish, fluffy and rapidly spreading
growth.
• Being an opportunistic infection, mucormycosis is produced by causative fungi in a
host whose immunological defense mechanisms are weakened by endogenous causes
like malignancy, leukemia, diabetes mellitus or exogenous causes like
immunosuppressive therapy.
VIRULENCE
The commonest encountered mucormycetes, Rhizopus arrhizus, has several
virulence factors like
• Angioinvasive nature
• Growth at or above body temperature
• Production of destructive enzymes
• Dormant spores which are resistant to destruction at extremes of temperature
• Active ketone reductase system and hydroxamate siderophores.
(In iron-limited conditions, Mucor activates a ketone reductase system to help
make hydroxamate siderophores. These special molecules bind tightly to iron
and help the fungus take it up from the environment. This process is essential for
the fungus to survive and grow during infection.)
 PATHOGENESIS

• Infection can occur by inhalation, percutaneous inoculation or ingestion. The spores

are inhaled into lungs where they are ingested by alveolar macrophages.
• These cells are known to inhibit germination of ingested spores to some extent but
their activity to kill them is limited.
• The increased risk of mucormycosis is in patients with ketoacidosis.
• Due to ketoacidosis, low serum pH diminishes the phagocytic effect of macro
phages, chemotactic and oxidative burst of neutrophils.
• The diabetic patients with ketoacidosis are usually more affected by mucormycosis.
• CotH proteins, which are present in Mucorales act as the fungal ligands that bind to
GRP78 during invasion of endothelial cells
• Rhizopus species have an active ketone reductase system and thrive in high glucose
and acidotic conditions.
• These patients also have decreased phagocytic activity because of an impaired glutathione
pathway.
• The normal serum inhibits Rhizopus whereas serum from patients of diabetic ketoacidosis
stimulates its growth.
• Patients on dialysis and iron overload, who are being treated with deferoxamine, an iron
chelator, are more susceptible to mucormycosis. It is probably because Mucorales use this
chelator as a siderophore to obtain more iron.
• The other risk factors include neutropenia, high-dose systemic steroids, protein-calorie
malnutrition, solid organ and bone marrow transplants, immunodeficiency, leukemia and
intravenous drug abusers who may inject spores of Mucorales with the drugs and then
present with space occupying lesions of central nervous system.
• Mucormycetes have a predilection for elastic lamina of large and small arteries causing
thrombosis, hemorrhage and infarction.
 CLINICAL FEATURES
Mucormycosis is a very rapidly progressive disease thereby may prove fatal if timely
diagnosis is not made entailing delay in institution of specific treatment.
It presents as following six clinical types on the basis of anatomical site involved in a
particular patient.
1. Rhinocerebral Mucormycosis
2. Pulmonary Mucormycosis
3. Cutaneous Mucormycosis
4. Gastrointestinal Mucormycosis
5. Isolated Renal Mucormycosis
6. Disseminated Mucormycosis
 RHINOCEREBRAL MUCORMYCOSIS
• It is invariably associated either with acute onset of diabetes mellitus, hyperglycemia
and ketoacidosis or with debilitating diseases such as leukemia and lymphoma.
• It spreads from nasal mucosa to turbinate bones, paranasal sinuses, orbit and palate
with eventual extension into brain where massive invasion of blood vessels cause
major infarct. The destruction of bones is often revealed by imaging techniques like
CT or MRI.
• The presenting symptoms include facial pain, head ache, lethargy and in advanced
cases, loss of vision.
• The physical examination reveal brownish, bloodstained nasal discharge on the
affected side, black eschar on palate due to hemorrhage and tissue necrosis, fixed and
dilated pupil and global proptosis and ptosis with dysfunction of cranial nerves.
• Sometimes, spread may also occur to lungs, gastrointestinal tract, skin and
occasionally to other organs. The Rhinocerebral mucormycosis is usually fatal
as patient dies within a week’s time and invariably diagnosed on autopsy.
• The fungi invade blood vessels and cause necrotizing vasculitis, resulting in
thrombosis of vessel lumen.
 PULMONARY MUCORMYCOSIS
• The mucormycetes may present as pulmonary disease through inhalation of
sporangiospores.
• The invasion of blood vessel may result to destruction of lung parenchyma.
• The clinical manifestations are non- specific and may include chest pain, dyspnea and
hemoptysis. The chest X-rays show evidence of infiltration, usually involving an
anatomical segment but typically progressing to involve multiple adjoining areas in the
same lung.
 CUTANEOUS MUCORMYCOSIS
• The clinical manifestations of cutaneous mucormycosis are varied and range
from pustules or vesicles to wounds with wider areas of necrotic zones. In their
early stages, lesions resemble ecthyma gangrenosum; cotton-like growth may
be seen over surface of tissues, a clinical sign known as ‘hairy pus’.
• The primary cutaneous lesions have rarely been reported which is due to direct
inoculation of fungus into skin. It usually occurs in patients with severe burns,
superficial ulcers in diabetics, gangrenous cellulitis in trauma patients.
• The lesions are painful progressively enlarge with nodular ecchymotic areas of
cutaneous infarction.
• Cutaneous mucormycosis has a much more favorable prognosis than more
deeply invasive forms but it is still associated with significant fatality and long
term morbidity. Cutaneous mucormycosis may also be observed as a
manifestation of disseminated disease in patients with leukemia.
PRIMARY CUTANEOUS MUCORMYCOSIS

Nodular Ecchymotic area Gangrene

 GASTROINTESTINAL MUCORMYCOSIS
• It is primarily found among patients suffering from extreme malnutrition and
is believed to be acquired by ingesting food contaminated with fungal
spores.
• Ingestion of fermented milk, porridge and alcohol made from corn and
herbal products has been implicated in gastrointestinal mucormycosis.
• The lesions in stomach are followed by colon, ileum and esophagus. This
may follow surgery from filthy trauma to abdomen or contaminated
ileostomy.
• Ulceration of gastric mucosa with thrombosis of associated vessels are
observed.
• Some non specific symptoms like abdominal pain, diarrhea, hematemesis
and melena can be seen.
ISOLATED RENAL MUCORMYCOSIS
• The isolated renal mucormycosis is one of the emerging clinical entity,
which is an unusual cause of renal infarction.
• The patients usually present with flank pain, fever and pyuria. In due course
of time there is infarct of renal tissue leading to hematuria.
• In the immunocompromised patients there are clinical features of acute
pyelonephritis.
• The overall survival of isolated renal mucormycosis is around 65% and
mortality is almost cent percent for those who have not undergone
nephrectomy.
 DISSEMINATED MUCORMYCOSIS

• The mucormycetes may become widely disseminated affecting lungs, kidney,

gastrointestinal tract, heart and brain however lungs being the most commonly
involved site.
• The clinical syndromes most frequently reported include pneumonia, stroke,
subarachnoid hemorrhage, brain abscess, cellulitis or gangrene of a skin
structure.
• In addition, gastrointestinal bleeding, peritonitis, acute myocardial infarction,
hepatitis and superior vena cava syndrome have been related to mucormycosis.
• The vessel invasion with infarction of surrounding parenchyma is seen with a
striking absence of inflammatory cells.
• Cerebral dissemination is caused by hematogenous and lymphogenous seeding
by abscess formation, particularly in intravenous drug abusers.
• Disseminated infections like endophthalmitis and prosthetic mitral valve
mucormycosis have also been established due to Mucor species.
 LABORATORY DIAGNOSIS
Direct Examination:
Specimen: Nasal discharge, skin scrapping, biopsy of infected gastric mucosa,
corneal discharge
KOH wet mount: A small piece of the excised tissue or BAL/sputum are kept
in the 20% KOH, shows characteristic broad non-septate (10-20 µm), ribbon-
like hyphae with wide-angle or right-angle branching at irregular intervals. The
calcofluor white stain, H&E stain, Gridley, Gram's and GMS stain can also be
used.

fluorescent brightener
 Fungal Culture
• The mucormycetes can be easily grown on conventional media like SDA with
antibiotics at both temperatures i.e. 25°C and 37°C.
• In about fifty percent of cases there is no growth despite direct demonstration of
the fungi.
• BHI broth may also be used where biopsy material is inoculated.
• The rapidly growing mycelial colonies are floccose, dense and have hairy
appearance.
• The mycelia are described as fibrous or cotton-candy growth, which is very
vigorous hence some of mucormycetes of order Mucorales are called as ‘lid-lifters’
as they press upon lid of petri dish from below.
• Microscopic examination of growth confirms coenocytic nature of hyphae and
sporulating species produce characteristic sporangia that contain from 50 to
100,000 sporangiospores.
• Czapek Dox agar and slide culture in humid atmosphere are tried for induction of
 MOLECULAR METHODS

• PCR
• Real Time PCR targeting CotH gene
 COVID 19 AND MUCORMYCOSIS

• There are multiple possible contributing factors for the development of

mucormycosis among patients with COVID-19 and these include diabetes
mellitus, obesity, use of corticosteroid, and the development of cytokine storms.
• The triad of SARS-CoV-2, steroid and uncontrolled diabetes mellitus have
contributed towards a significant increase in the incidence of angioinvasive
mucormycosis.
• In March 2021, 41 cases of COVID-19 associated mucormycosis has been
reported worldwide.
• COVID-19 is also associated with immune dysfunction preventing the
polymorphonuclear phagocytes from attacking the fungal spores upon entry.
• Patients with severe COVID-19 also require a prolonged hospital stay and
mechanical ventilation; the occurrence of fungal spores in this equipment could
also contribute to mucormycosis in these individuals.
• The immunosuppressants and corticosteroid medications that are
warranted in COVID-19 can contribute significantly to the occurrence of
mucormycosis.
• Further, in addition to hyperglycemia, COVID-19 also contributes to
changes in iron metabolism.
• High ferritin levels have been observed in COVID-19, the high iron
concentrations release reactive oxygen species while damaging the nearby
tissue.
• The cytokines released during COVID-19 further increases intracellular
iron and leakage of iron into the circulation, posing as a risk factor for the
development of mucormycosis
 TREATMENT AND PROPHYLAXIS
• The combination of surgical debridement and antifungal drugs is required for
an ideal treatment of mucormycosis.
• There are only few drugs, which are available for treating mucormycosis i.e.
intravenous amphotericin B, posaconazole and isavuconazole.
• Surgical debridement is the mainstay of therapy for cutaneous mucormycosis
and topical amphotericin B is a useful adjunct in concentration of 5 mg/ml,
which is applied with a gauge.
• Skin grafting to repair defects remaining after healing of surgical wound is
usually successful.