The document discusses mucormycosis, an infection caused by fungi of the order Mucorales. It covers the etiology, risk factors, clinical presentations, diagnosis, and management of mucormycosis. The key points are: - Mucormycosis occurs in immunocompromised individuals and those with conditions like diabetes or neutropenia. - Rhizopus is the most common causative genus. Transmission is usually through spore inhalation. - Clinical manifestations depend on site of infection, which can include sinuses, lungs, and gastrointestinal tract. - Diagnosis involves microscopic examination of tissues and molecular methods like PCR. - Treatment requires

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4. • Introduction
• Why we are discussing this?
• “PRINT Media” – as a source of information
• “Experts view”
• Epidemiology
• Etiology
• Risk factors
• Clinical Presentations
• Diagnosis
• Management
• Prognosis

24. • Demographic Data
• Agent factor –
• Etiology / Source of infection/ Portal of entry
• Host factor
• Predisposing factors/ Risk factors
• Environment factor
• Virulent factor

27. • Mucormycosis is an infection caused by several species of
filamentous molds belonging to the order Mucorales.
• The infections usually occur in immunocompromised individuals
with one or more underlying conditions.
• The fungi responsible for these infections are found in different
environmental niches like soil, decaying vegetables, bread, and even
dust.
• Some of the risk factors associated with mucormycosis include
conditions like uncontrolled diabetes mellitus, bone marrow
transplant, neutropenia, trauma, burns, and hematologic
disorders.

28. • Studies related to mucormycosis have increased over the years due to
the severity of these infections, with a high rate of mortality.
• Some of the species belonging to the order Mucorales are Rhizopus,
Mucor, Rhizomucor, Apophysomyces, etc. Rhizopus is the most
common species associated with mucormycosis, closely followed by
Mucor and Lichtheimia.
• The infections can be characterized by different clinical
manifestations depending on the site of infection and the severity.
• Some of the common sites of infections by Mucorales include
sinuses, lungs, skin, and gastrointestinal tract.

29. • Mucormycosis has also been associated with molds from the order
Entomophthorales; however, these infections are not angioinvasive
and do not disseminate. Such molds result in chronic subcutaneous
infections even in immunocompetent hosts.

30. • The fungal species belonging to the order Mucorales can be found
throughout the environment in different sources ranging from soil to
vegetables.
• Even though these species are ubiquitous in distribution, they are
predominantly saprobic soil organisms.
• The fungi can be commonly found in soil than in air as these exist in
the form of spores in order to protect themselves as well as to assist
the process of dispersal. The occurrence thus is more prevalent in
tropical areas.

31. • The dispersal and occurrence of these species are more common
during summer than in winter as the fungal spores thrive in dry and
arid conditions.
• Besides, some of these fungi can also occur in decaying matter like
decaying vegetables and fruits as these are good sources of
carbohydrates that are essential for the growth and survival of the
species.
• Mucoralean fungi usually reproduce anamorphically via non-motile
sporangiospores released from different sporangia.
• Some of the Mucoralean fungi can also occur as parasites of plants,
fungi, and animals, resulting in different forms of diseases.

32. • The fungal species that are most frequently isolated from patients with
Mucormycosis are Apophysomyces, Cunninghamella, Lichtheimia,
Mucor, Rhizopus, and Rhizomucor.
• The etiology of these infections differs considerably in different
countries, but Rhizopus spp is the most common cause of these
infections in most parts of the world.
• These species exist as spores and thrive in dry, humid, and arid
conditions. These transmit through the air and result in mild to
severe infections in immunocompromised individuals.
• The species present in the order Mucorales display only a small
number of distinguishable morphological characteristics that can be
used to distinguish between themselves.

33. • Most of these species are differentiated based on characteristics
like structure, size, and shape of the sporangia, color and state of
the spores, and the mycelium.
• The Mucoralean fungi are defined by usually abundant and rapidly
growing mycelium and other anamorph structures.
• The mycelium is unsepted or irregularly septed, and the anamorphic
sporangiospores produce multi-spored sporangia.
• Structures like chlamydospores, arthrospores, and yeast cells are
rare in these species. The sporangia consist of the variously shaped
columella.
• Some species might exhibit appendages that enable them to switch
between the filamentous multicellular state and the yeast-like state.

35. • There is a difference in virulence across different species belonging to
the order Mucorales, which indicates an array of virulence factors,
resulting in aggressive invasive disease in some species and infrequent
mortality in others. The following are some of the virulence factors
employed by the fungal species responsible for mucormycosis

36. • Mucoralean fungi flourish in iron-rich environments as iron is
required for cell growth and development as well for different vital
processes in the cell.
• It has been observed that the increased level of iron in the serum
plays an important role in predisposing patients to mucormycosis.
• Fungi take up the iron from the blood by using iron permeases or
chelators and reduce them from ferric to the more soluble ferrous
form.
• The ferrous iron generated from the permeases is then captured by a
protein complex made up of multicopper oxidase and a ferrous
permease.
• The iron take-up by the fungi is essential for enhancing the growth and
development of the fungi and increasing their pathogenicity.

37. • High-affinity iron permease plays an essential role in iron uptake and
transfers within the fungal species, especially in environments with a
lack of iron.
• The FTR1 gene is highly expressed in the species during infection
by Rhizopus oryzae, and the knockdown of the gene is known to
reduce the virulence of the species.
• The permeases occur in fungi as a part of a reductive system containing
redundant surface reductases involved in the reduction of ferric to
the soluble ferrous form.

38. • Rhizoferrin is a siderophore secreted by Rhizopus as a part of the
polycarboxylate family. The siderophore is responsible for the supply
of iron through a receptor-mediated, energy-dependent process.
• However, siderophore on its own is inefficient in obtaining iron from
the serum and requires the involvement of the organisms’ endogenous
siderophores for virulence.
• In some Mucoralean fungi, the fungus utilizes xenosiderophores like
deferoxamine in order to effectively obtain iron from the host.

39. • Calcineurin is calcium and calmodulin-dependent serine/threonine
protein phosphate that is an essential virulence factor in the
pathogenesis of Mucorales.
• It is involved in the transition of Mucor circinelloides from the yeast
form to hyphae. The spores of the species are capable of inhibiting
phagosomal maturation by macrophages, unlike the yeast cells.
• Calcineurin is also closely related to protein kinase A activity which
is an equally important factor for the pathogenesis of M. circinelloides.

40. • Spore coat protein is also a virulence factor that is found universally on
the spore of all Mucorales.
• The protein plays an important role as invasions during the
pathogenesis of mucormycosis.
• It also disrupts and damages immune cells and acts as a specific
ligand for the GRP78 receptor.

42. Figure: Diagram depicting the interactions of Mucorales with endothelial cells during
hematogenous dissemination/organ seeding and the effect of host factors on these
interactions and on the immune response.
(A) Hyperglycemia and ketoacidosis result in liberation of iron from serum-
sequestering proteins (e.g., transferrin) via glycosylation and protonation, respectively.
(B) Ketone bodies (e.g., β-hydroxy butyrate [BHB]) and free iron negatively affect the
immune response to the infection, while sodium bicarbonate (NaHCO3) reverses this
negative effect by preventing iron release from transferrin and neutralizing acidity.
(C) Surface expression of glucose-regulator protein 78 (GRP78) on endothelial cells is
enhanced to cope with the stress elicited by hyperglycemia, free iron, and ketone
bodies.
(D) Glucose, free iron (transported by the high-affinity iron permease [Ftr1p]), and
BHB also enhance the expression of fungal cell surface CotH, which results in the
invasion of the endothelium and augmentation of fungal growth.
(E) In deferoxamine-treated hosts, the iron-rich ferrioxamine binds to its fungal
receptor (ferrioxamine binding proteins [Fob1/Fob2]) then releases iron via a reductive
step prior to feeding invading Mucorales via Ftr1p transportation. Image
Source: PLOS Pathogens.

43. • Mucormycosis is acquired by immunocompromised individuals, mostly by
the inhalation of fungal spores from the environment.
• The primary mode of transmission of Mucorales is the inhalation of
sporangiospores. Other modes of transmission include ingestion of the
spore or inoculation of conidia from wounds or trauma.
• Nosocomial outbreaks of infections can also occur; however, these are
quite rare. Nosocomial infections are associated with contaminated
bandages, medical equipment, and ventilation.
• The mode of transmission of the fungi from one individual to the other
depends on the site of infection and the severity of infection.
• Rhinocerebral mucormycosis transmits mostly via the inhalation of spores
or droplets, whereas cutaneous mucormycosis transmits via close personal
contact.

48. • The pathogenesis of mucormycosis begins with the inhalation or
ingestion of spores from the environment.
• The entry of the spores into healthy individuals results in
phagocytosis of the spores with the help of polymorphonuclear
phagocytes.
• The persistence of the fungi and their growth is facilitated by defects
in the phagocytic activity of the immune cells.
• Conditions like hyperglycemia and acidosis affect chemotaxis and
phagocytic killing by the immune cells.
• Fungi like Rhizopus secrete the enzyme ketone reductase that
supports the growth of fungi in acidic and glucose-rich
environments like ketoacidosis.

49. • The increased virulence in the fungal species results in inherent
resistance in these species to human phagocytes.
• Similarly, iron metabolism also plays an important role in the
pathogenesis of mucormycosis. Different factors in the fungal species
like the iron permeases, rhizoferrin, etc., help in the transition of
ferric into soluble ferrous.
• The presence of iron in the serum further supports the growth and
survival of the species in the human body.
• The fungi then slowly make their way into the bloodstream by
invading blood vessels with resultant thrombosis and tissue
necrosis.
• The host-pathogen interaction further results in extensive
angioinvasion with ischemic necrosis and tissue damage.
•

50. • The movement of the organisms through endothelial cells and the
extracellular matrix is the most critical step in the pathogenesis of
fungal species like R. oryzae.
• The binding of the organism to the host endothelial cells results in
endocytosis of the organism, which damages the endothelial cells.
It has been recently understood that glucose-regulated protein
(GRP78) acts as a receptor to mediate the penetration and
damage of these cells.
• Since mucormycosis can occur due to a number of fungal species, the
exact mechanism of disease or pathogenesis might not be the same for
all species.
• Besides, the dissemination of the organism to a different part of the
body can result in different forms of mucormycosis.

52. Figure: A diagram showing the molecular pathogenesis of the two main
manifestations of mucormycosis.
(A) R. delemar inhaled spores are trapped in the sinus cavities of patients
with DKA due to the overexpression of GRP78 on nasal epithelial cells,
and the interaction with fungal CotH3 results in rhinoorbital/cerebral
mucormycosis. Colored circles represent elevated levels of glucose, iron,
and ketone bodies.
(B) In immunosuppressed patients, inhaled spores reach the alveoli and
bind to integrin α3β1 via fungal CotH7, thereby triggering activation of
EGFR and subsequent invasion and pulmonary infection. Image
Source: mBio, American Society for Microbiology.

56. OXYGENTHERAPY

66. • The diagnosis of mucormycosis infections requires a high degree of
suspicion, recognition of host factors, and proper assessment of
different clinical manifestations.
• Early diagnosis of these infections can be taken as a possible method
of prevention of severe conditions and mortality.
• Since the infections can occur in practically all organs, a syndrome-
oriented approach to diagnosis is not very effective.
• The following are some of the modes of laboratory diagnosis of
mucormycosis;
• Microscopic Examination
• Serology
• Molecular Assay

67. • The first step in the diagnosis of mucormycosis is the microscopic
examination of different clinical specimens.
• The species belonging to the order Morales have nonseptate or pauci-
septate hyphae with variable width.
• Stains like Periodic acid Schiff or Grocott-Gromori’ methenamine
silver can be used used to highlight the fungal hyphae and observe the
morphology clearly.
• Invasive infections can be characterized by angioinvasion that can be
observed in terms of the increased number of phagocytic cells like
neutrophils and other granulocytes.
• Even if direct examination of clinical specimens is a quick and simple
method, the histopathological examination cannot allow the
differentiation of some species

68. • Serological tests like ELIZA, immunoblots, and immunodiffusion
tests can be performed for the diagnosis of mucormycosis with
variable success.
• Mucorales-specific antibodies can be detected by the enzyme-linked
immunospot assay to diagnose invasive mucormycosis.
• The process is, however, not very common as the antibodies specific to
different fungal species are difficult to find and develop.

69. • Molecular assays including PCR, restriction fragment length
polymorphism, and DNA sequencing provide the most reliable form
of diagnosis of Mucorales.
• Most of the molecular-based diagnostic tools use an internal
transcribed spacer or the 18S rRNA genes.
• The methods are still quite new, and there haven’t been enough data to
specify the sensitivity and specificity of the tests.
• Molecular diagnosis with the blood and serum samples has been
proposed and shown promising results.

70. • The successful treatment of mucormycosis is based on a multi-step
approach which requires reversal of underlying conditions, early
administration of antifungal agents at optimal dosages, and
removal of all infected tissues.
• In patients with uncontrolled diabetes and suspected mucormycosis,
rapid correction of metabolic abnormalities is a must.
• The use of corticosteroids and other immunosuppressive drugs
should be tapered to the lowest dose possible.
• The success of the treatment of mucormycosis depends on the early
diagnosis of the disease with prompt initiation of therapeutic
interventions.

71. • Mucorales can be resistant to most antifungal agents like
voriconazole, but Amphotericin B is the most effective drug for
most Mucorales.
• Other drugs include Posaconazole, Isavuconazole, itraconazole, and
terbinafine with different degrees of activity against Mucorales.
• The medicinal therapy has to be introduced immediately once the
infection is suspected due to the potential for the rapid spread of the
infection.
• The optimal dose for these antifungal drugs is still in question;
however, some guidelines have been proposed to provide the
appropriate dose and concentration of these drugs.
• The prevalence of intravenous and tablet forms of these drugs has
increased bioavailability and drug exposure.

72. • Other forms of treatment include surgeries when needed. Removal of
not just the necrotic tissues but also surrounding infected healthy
tissues might be required.
• Surgery is often required in rhinocerebral mucormycosis and soft
tissue infections. Surgeries might also be helpful in the single
localized pulmonary lesion.
• Other forms of medical therapy include the use of hyperbaric oxygen
to prepare a more oxygen-rich environment and the
administration of cytokines along with antifungal agents.

73. • The high mortality rate of these infections indicates the need for early
intervention with immunocompromised individuals.
• It is important that the patients are aware of the infections and their
presentations so that they can make an early visit to the hospital.
• Prevention and control of these infections are based on the early
diagnosis of the disease and the maintenance of a proper immune
system.
• Individuals at risk with different underlying conditions should be
careful about any possible symptoms and other conditions.
• It has been recommended that the patients take appropriate drugs
assigned for their underlying conditions in order to maintain their
health.

74. • The control of the disease can also be made by the use of masks in
areas that might contain the spores the causative agents.
• It is imperative to maintain a healthy diet and appropriate lifestyle
in order to prevent severe cases of infection.
• Do not use wet masks.
• Do not contain fruits and vegetables at home.
• Hand hygiene and use of hypertonic saline
and betadine for throat and nasal
disinfection.

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