INTRODUCTION

The ascent of man has been accompanied by the birth of science,

resulting in the emergence of various inventions and discoveries. The

concomitant development of sophisticated technology coupled with

mankind’s thirst for knowledge and his curiosity to seek the ultimate truth

has enabled him to diagnose and treat serious diseases previously

thought to be incurable.

However certain diseases continue to prove a challenge to him.

One such condition is fungal infection. More than ever, fungal diseases

have emerged as a major challenge for physicians, clinical microbiologists

and scientists. The incidence of mycotic infection and the number and

diversity of pathogenic fungi have increased dramatically in the recent

years. Both imrnunocompetent and immunocompromised individuals are

at risk.

The growing breadth, complexity and significance of mycological

disease needs an in depth study of treatment of fungal rhinosinusitis that is

increasing in incidence and often difficult to diagnose and manage.

Fungal rhinosinusitis follows inhalation of fungal spores into the

nasal passages. Occasionally, however the fungal cells can invade from

the pre-existing infection in the lungs or elsewhere in the body. Most

infections of the sinuses affect not only the paranasal sinuses but also the

nose.

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The American academy Of Otolaryngology’s task force on

rhinosinusitis suggested the term ‘rhinosinusitis’ more accurately

describing the disease process than the term sinusitis. A number of

conditions and disease modalities are recognized to increase susceptibility

to mycotic infections. In general, people with impaired cell mediated

immunity are more susceptible to mycotic infections. This condition may

be congenital or induced by other diseases such as AIDS, Diabetes

mellitus or hematogenous dyscrasias or by administration of cytotoxic

drugs to manage cancer or transplantation. It is important to classify fungal

rhinosinusitis to accurately predict diagnosis and optimize effective

therapy.

In 1997, deShazo classified it into invasive and non-invasive forms.1

Then he characterized five major types .The first of the non-invasive forms

were allergic fungal sinusitis as well as sinus fungal ball. Of the invasive

forms the most common form is what he described as acute or fulminant

invasive sinusitis. Then he described chronic invasive fungal rhinosinusitis,

and finally granulomatous invasive fungal rhinosinusitis. All these

manifestations overlap or progress from a non-invasive form to an invasive

form, if the immunogenic status of the patient changes. This prognosis is

less dependent on a particular fungus causing the infection than on

immunogenic status of the host.

Knowledge of fungal organisms is important in directing appropriate

antifungal therapy and possibly in selecting the correct antigens for post-

surgical immunotherapy in allergic fungal rhinosinusitis. For the diagnosis

of fungal rhinosinusitis, a thorough clinical examination, KOH mount of

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nasal discharge, fungal cultures, histopathological examination, serological

and skin tests and coronal CT scans of the patients are necessary.

Various approaches to manage fungal rhinosinusitis include surgical

debridement, topical and systemic corticosteroids, topical and systemic

antifungals and immunotherapy.

This study aims at highlighting the presently available modalities of

treatment depending upon the type of fungal infection and host-immune

status.

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AIMS AND OBJECTIVES

The study was carried out with the following aims in mind.

1. To carry out a clinical study of fungal rhinosinusitis in its various

presentations.

2. To correlate various factors pertaining to etiology of the disease with

reference to:

• Age

• Sex

• Predisposing factors

• Immunological status

3. To evaluate the criteria for selection of patients for surgery.

4. To study various treatment modalities.

5. To compare and evaluate the efficacy of various medical and surgical

treatment modalities in our tertiary health-care centre.

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ANATOMY OF NOSE AND PARANASAL SINUSES 2

External nose is a surface projection of the face. It is a triangular

pyramid shaped structure with its root above and base directed

downwards. The nose has two openings, the anterior nares separated by

the columella. The apex is connected to the root by septum, upper part of

which is termed bridge. Each side of the nose ends in a rounded

eminence, the ala-nasi which forms the outer boundary of anterior nares.

The supporting framework of external nose consists of a bony

pyramid and a number of paired and unpaired cartilages. The bone

consists of the anterior part of the body of maxilla with its frontal process,

the nasal spine of frontal bone and the nasal bones. The cartilages which

complete the framework of the nose are a single central septal cartilage,

two upper nasal cartilages and two lower nasal alar cartilages.

The muscles bringing about the movement of the ala and the lower

part of the septum are the procerus, the nasalis consisting of a transverse

part (compressor naris) and an alar part (dilator naris); and the depressor

septi. The muscles are either attached to the cartilage, or pass across the

nose from the maxilla to a central aponeurosis. The muscles are

rudimentary in man. The upper buccal branches of facial nerve innervate

all of the above muscles. The skin of the dorsum and sides of the nose is

thin and loosely connected with the subjacent part; but over the ala it is

thicker and more firmly adherent, and is furnished with numerous large

sebaceous glands, the orifices of which are usually very distinct.

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Nasal cavity:

It extends from the external nares or nostrils to the posterior

choanae, where it becomes continuous with the nasopharynx and is

narrower anteriorly than posteriorly. Vertically it extends from the palate to

the cribriform plate, being broader at its base than superiorly where it

narrows at the olfactory cleft. The nasal cavity is divided in two by a

septum. Each half has a floor, a roof, a lateral wall and a medial (septal)

wall.

Floor:

The floor is concave from side to side, anteroposteriorly flat and

almost horizontal. Its anterior three quarters are composed of palatine

process of maxilla, its posterior one quarter by the horizontal process of

the palatine bone. About 12 mm behind the anterior end of the floor is

slight depression in the mucosa overlying the incisive canals. It contains

the terminal branches of the nasopalatine nerve, the greater palatine

artery and a short mucosal canal (Stenson’s organ).

Roof:

The roof is narrow from side to side, except posteriorly and may be

divided into frontonasal, ethmoidal and sphenoidal parts, related to the

respective bones. As both the sphenoidal and frontonasal parts of the roof

slope downwards, the highest part of the nasal cavity relates to the

cribriform plate of the ethmoid which is horizontal. This area is covered by

olfactory epithelium (Schneiderian membrane) which spreads down a little

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distance onto the upper lateral and medial walls of the nasal cavity. The

rest of the nasal cavity (with the exception of the nasal vestibule) is lined

by respiratory mucous membrane and is continuous with that of the

paranasal sinuses, nasolacrimal duct and nasopharynx.

Nasal septum:

The nasal septum is composed of a small anterior membranous

portion, a single quadrangular cartilage and several bones: the

perpendicular plate of ethmoid, the vomer and two bony crests of maxilla

and palatine bones.

The cartilaginous portion is composed of a quadrilateral cartilage

with a contribution from the lower and upper lateral alar cartilages forming

the anterior nasal septum. Its upper margin is expanded and connected to

the upper lateral cartilages, forming the anterior septal angle, just cranial

to the domes of the lower lateral cartilages. It abuts the maxillary spine at

the inferior septal angle. Anteriorly, it is attached by a thin membranous

septum to the medial crura of lower lateral cartilages.

The perpendicular plate of the ethmoid forms the superior and

anterior bony septum and is continuous above with the cribriform plate and

crista galli. The vomer forms the posterior and inferior bony nasal septum

and articulates by its two alae with the rostrum of sphenoid. The inferior

border of the vomer articulates with the nasal crest formed by the maxillae

and palatine bones. The anterior border articulates with the perpendicular

plate above and the quadrilateral cartilage inferiorly. The posterior edge of

the vomer forms posterior free edge of the septum.

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The lateral nasal wall:

Inferior meatus:

Inferior meatus is that part of the lateral wall of the nose which lies

lateral to the inferior turbinate.3It is the largest meatus extending almost

the length of the nasal cavity. The meatus is highest at the junction of the

anterior and the middle third. In adults this ranges from 1.6 to2.3mm at

1.6cm along the bony lateral wall. The nasolacrimal duct opens into the

inferior meatus usually just anterior to its highest point.4 There is no true

valve, the opening being guided by small folds of mucosa. It can be

identified by gentle massage of the lacrimal sac at the medial canthus.

Inferior turbinate:

This structure is composed by a separate bone, the inferior concha

which has an irregular surface and is perforated and grooved by the

vascular channels to which the mucoperiosteum is firmly attached. The

bone has a maxillary process which articulates with the inferior margin of

the maxillary hiatus. It also articulates with the ethmoid, palatine and

lacrimal bones, completing the medial wall of the nasolacrimal duct.

Middle meatus:

The middle meatus is that portion of the lateral wall lying lateral to

the middle turbinate. It receives drainage from the frontal, maxillary and

anterior ethmoidal sinuses.

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Middle turbinate:

The middle turbinate is much larger and extends from atrium to the

level of choana. It is crucial to understand the anatomy of the ethmoid

complex. Most anteriorly the turbinate attaches to the maxilla just anterior

to which is the bulge of the agger nasi. The anterior third attaches to the

skullbase vertically at the lateral border of the cribriform niche with the

frontal bone forming the root of the ethmoids. The posterior third attaches

horizontally to the lamina papyracea and the medial wall of the maxilla.

Between the two portions of the turbinate, there is an obliquely disposed

plate of bone, the basal lamella of the middle turbinate, attaching laterally

to the lamina papyracea.

The uncinate process:

This thin crescent of bone curves posteriorly, parallel to the curve of

the anterior face of the ethmoidal bulla.

Hiatus semilunaris:

The Hiatus semilunaris is a two dimensional space lying between

the posterior edge of the uncinate process and the anterior surface of the

ethmoidal bulla.

Ethmoidal infundibulum

The ethmoidal infundibulum is a three dimensional funnel

connecting the natural ostium of the maxillary sinus to the middle meatus

via the Hiatus semilunaris. The natural ostium of the maxillary sinus lies at

the floor of the ethmoidal infundibulum, usually at its middle and posterior

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third so is not usually visualized until the uncinate process has been

removed.

The frontal recess:

The frontal recess is found in the anterosuperior-most portion of the

middle meatus. The term frontonasal duct has been generally abandoned

as no true duct exists histologically or topographically in most people. The

natural ostium of frontal sinus is somewhat variable in its configuration but

most frequently it presents as an hourglass narrowing opening directly into

the recess.

The ethmoidal bulla:

This is one of the most constant features in the middle meatus

containing the anterior ethmoidal cell but it may be poorly aerated or

completely unpneumatised in 8% of patients.5 The anterior face forms the

posterior margin of the Hiatus semilunaris and ethmoidal infundibulum.

Posteriorly the bulla may fuse with the basal lamella of the middle

turbinate and superiorly it may reach the roof of the ethmoids forming the

posterior wall of the frontal recess.

Superior meatus:

This meatus is again defined by its relation to the superior turbinate.

The posterior ethmoidal cells open into this region.

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Supreme turbinate:

A Supreme turbinate is discernible above the superior meatus in

60-67%of patients.

Sphenoethmoidal recess:

Sphenoethmoidal recess lies medial to the superior turbinate and is

the location of the ostium of the sphenoidal sinus.

The Maxillary sinus:

The maxillary sinus is the largest of the paranasal sinuses. It is a

pyramidal cavity within the body of the maxilla. The apex is directed

laterally and extends into the zygomatic process of maxilla. The base is

directed medially and is formed by lateral wall of the nose. Floor of the

sinus is formed by alveolar process of maxilla. The roof is formed by

orbital surface of maxilla and is ridged by canal of the infraorbital nerve.

The floor lies about 1-1.2cms below the level of nasal cavity in

adult. The average measurements are height 3.5cms, breadth2.5cms and

depth 3.2cms.The sinus communicates with the lower part of the hiatus

semilunaris through an opening in the anterosuperior part of its base.

Accessory ostia if present lie behind the main one.

The Ethmoidal sinus:

It consists of number of thin walled cavities within the lateral

masses of ethmoid bones, and sometimes in agger nasi and middle

turbinate. The ethmoidal sinus is divided into anterior and posterior cell

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groups by the basal or ground lamella of the middle turbinate. Cells

anterior to the middle meatus are generally smaller and open into middle

meatus, whereas the larger cells open posteriorly through the superior or

supreme meatus into the sphenoethmoidal recess. The anterior cells are

generally smaller and more numerous (2-8) than the posterior group (1-5).

The largest form the bulla ethmoidalis and most anterior cells form the

agger nasi opening directly into the middle meatus. The posterior cells are

large and pyramidal in shape, pointing towards the orbital apex. They are

closed posteromedially by the sphenoid bone.

The posterior-most ethmoidal cells can extend supero-lateral to the

sphenoid upto 1.5cms posterior to the anterior wall of sphenoid. This

configuration was originally described by Adolf Onodi in 1903, and bears

his name. The ethmoidal cells may pneumatise the orbital floor, forming

Haller cells which can encroach upon the ethmoidal infundibulum.

The roof of ethmoid sinus is formed by the floor of the anterior

cranial fossa and may be horizontal or sharply down-sloping medially. The

floor of the anterior cranial fossa creates a large difference between the

height of the cribriform plate medially and the ethmoidal roof laterally. The

roof is also thin medially and may have a significant area of dehiscence

adjacent to the ethmoidal vessels.

The Frontal sinus:

The frontal sinuses are found in the frontal bone deep to the

superciliary ridges. The two sinuses are unequal in size and have the

shape of the pyramid with its apex upwards. They are separated by a thin

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septum of bone which is seldom in midline and may occasionally be

deficient. Their average height is 2cms, breadth 2.5cms and depth 2cms.

The anterior wall is formed by diploic bone and is the thickest of the walls.

The posterior wall is thinner but is composed of more compact bone. The

floor slopes medially downwards and backwards towards the opening of

frontonasal duct. The duct runs down through the front of the ethmoidal

labyrinth and enters either the infundibulum or opens independently into

the anterior end of the middle meatus.

The Sphenoidal sinus:

They are two in number contained within the body of the sphenoid

bone and placed posterior to the upper part of nasal cavity. Laterally it is

related to the optic nerve and the cavernous sinus and its contents,

superiorly it is related to the undersurface of the frontal lobes and to the

olfactory tracts. The pituitary gland lies above and posteriorly. The sinuses

are separated by a septum which is seldom in midline, so they are rarely

symmetrical. Average measurements of the size of the adult sinus have

been given as height 2cms, breadth 1.8cms and depth 2cms. Occasionally

the sinus spreads laterally to invade the greater and lesser wing and

medial and lateral pterygoid plates of sphenoid and occasionally into the

basilar part of the occipital bone. Each sinus communicates with the

sphenoethmoidal recess in the superior meatus by an opening in the

upper part of the anterior wall.

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Mucous membrane of Nose and Paranasal sinus:

The Mucous membrane of nose is of two types:

1. Respiratory:

This lines the lower two-third of the nasal septum, the lateral wall of

the nose below the superior turbinate and the floor of the nasal fossa. It is

pink in colour, moist and is covered by a ciliated columnar epithelium. This

consists of tall ciliated epithelium which narrows in its deeper part.

Irregular basal cells fill in the intervening spaces. Goblet cells containing

thick mucus lie among the ciliated cells. Thin fluid comes from compound

acinar secreting glands of two types, serous and mucinous. Both types of

mucus are spread thin over the epithelium and propelled by cilia at a

density of 5 million per square mm. Cilia move at 14 beat per second and

in a healthy adult the mucociliary stream carries about a pint and half of

nasal mucus to the throat every 24 hrs.

A fibroblastic basement separates the epithelium from the

subepithelial tissue, which is loose and highly vascular and contains many

mucous and serous glands. Its deeper portion is firmly blended with the

underlying periosteum and perichondrium. The respiratory membrane

extends from the limen nasi throughout the nose and into the upper half of

the nasopharynx. It also extends into the sinuses through their ostia, and

is thinner there. It is also continuous with the epithelia of nasolacrimal duct

and Eustachian tube. Above it is continuous with the olfactory mucosa of

the nose. Anteriorly at the limen nasi it becomes continuous with the skin

of the nasal vestibule.

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2. Olfactory:

This (Schneiderian) membrane lines the upper one third of the

nasal septum, the roof of the nose, and the lateral walls above including

the superior turbinate. The olfactory epithelium is made up of non-ciliated

columnar epithelium and is yellowish in colour. It contains the serous

glands of Bowman. The cells are:

• Olfactory: Bipolar-The superficial process end at the surface of the

mucous membrane in bulbous process which bears the olfactory hairs.

The central process passes to the olfactory bulb through the cribriform

plate.

• Supporting.

• Basal: contain yellow pigment.

Blood supply of nasal cavity and paranasal sinuses:

Arterial supply:

The blood supply of the nasal cavity and paranasal sinuses is derived from

the branches of external and internal carotid arteries.

(1) Branches of external carotid artery:

• Sphenopalatine artery: via the internal maxillary artery supplies

the turbinates and meatus of the nose and most of the septum.

• Greater palatine artery: a branch of maxillary artery contributes

branches to the lateral nasal wall and to the anterior part of the

septum.

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• Superior labial artery: a branch of facial artery, sends branches to

the tip of the septum and the ala-nasi. Its anastomosis with the

branch of sphenopalatine artery and the greater palatine artery (the

artery of epistaxis) forms Kiesselbach’s plexus.

• Pharyngeal branches of internal maxillary artery: supplies the

sphenoidal sinus.

(2) Branches of internal carotid artery:

Anterior and posterior ethmoidal arteries: Branches of the

ophthalmic arteries. They supply the roof of the nose, anterior part of the

septum and lateral wall of the nose, and the ethmoidal and frontal sinuses.

Bleeding from these vessels is seen above the level of the middle

turbinate.

Venous drainage:

The veins form the cavernous plexus beneath the mucous membrane.

They open into-

• Sphenopalatine vein and anterior facial vein from the plexus.

• Ophthalmic veins from the ethmoidal veins.

• Veins on the orbital surface of the frontal lobe of the brain, through

foramina in the cribriform plate.

• Superior saggital sinus, through the foramen caecum.

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Nerve supply of the nose and paranasal sinuses:

Autonomic nerve supply:

This controls the vascular reactions of nasal mucous membrane.

Sympathetic fibres: Postganglionic fibres pass from the superior cervical

ganglion to the plexus around the internal carotid artery. They then form

the deep petrosal nerve which with the greater superficial petrosal nerve

becomes the nerve of pterygoid canal(Vidian nerve).They are distributed

without relay via the sphenopalatine ganglion .They maintain a constant

tonic vasoconstrictor action. Section of cervical sympathetic nerves cause

vasodilatation and results in stuffy nose.

Parasympathetic fibres: These are secretomotor to the glands via

branches from pterygopalatine ganglion

Nerve supply of the paranasal sinuses:

The ethmoidal sinuses are innervated by the anterior and posterior

ethmoidal nerves and orbital branches of pterygopalatine ganglion. The

sphenoid sinuses are supplied by posterior ethmoidal nerves and orbital

branches of pterygopalatine ganglion. The frontal sinuses are supplied by

supraorbital nerve. The maxillary division of the trigeminal nerve supplies

the maxillary sinus via the infraorbital, superior alveolar and greater

palatine nerves.

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Olfactory nerves:

The sense of smell is supplied by the 1st cranial nerve. Fibres arise

from bipolar cells in the olfactory mucosa. They are non-medullated and

pass through foramina in the cribriform plate. They enter the undersurface

of the olfactory bulb.

Lymphatic drainage of nose and paranasal sinuses:

The lymphatic vessels arise from a continuous network in the

superficial part of the mucous membrane. This is best developed at the

posterior end of the superior turbinate. Submandibular lymph nodes collect

lymph from the external nose and anterior part of the nasal cavity. Upper

deep cervical lymph nodes drain the rest of the nasal cavity, either directly

or through the retropharyngeal nodes.

DEVELOPMENT OF NOSE AND PARANASAL SINUSES

The external nose and paranasalcavity: 2

The nose develops from a number of mesenchymal processes

around the primitive mouth.6 The nasal cavity is first recognizable in the 5-

6 mm embryo in the 4th intrauterine week as the olfactory or nasal placode,

a thickening of the ectoderm above the stomatodeum. This placode sinks

to form the olfactory pits lying between the proliferating mesoderm of the

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medial and lateral nasal folds of the frontonasal process. This deepens to

form the nasal sac by the fifth week.

In the 12.5 mm embryo, the maxillary process of the first branchial

arch grows anteriorly and medially to fuse anteriorly with the medial nasal

folds and the frontonasal process which closes the frontonasal pits off to

form widely separated primitive nasal cavities. The primitive nasal cavity

and mouth are separated initially by a bucconasal membrane. This

gradually thins as the nasal sac extends posteriorly and eventually breaks

down at the 14-15 mm stage to form the primitive choanae. These are

more anteriorly placed than the definitive posterior growth of the

palate.7The floor anterior to the choanae forms from the mesenchymal

extensions of the medial nasal folds to produce the premaxilla and

ultimately the upper lip and medial crus of the lower lateral cartilages.

The palate and nasal septum:

The primitive palate begins to form anteriorly with fusion of the

maxillary and frontonasal processes by the 13.5 mm stage. A midline ridge

develops from the posterior edge of the frontonasal process in the roof of

the oral cavity and extends posteriorly to the opening of Rathke’s pouch.

This becomes the nasal septum which is continuous anteriorly with the

partition between primitive nasal cavities enlarge, the palatal processes

derived from the lateral maxillary mesoderm grow medially towards each

other and the septum. Initially they lie lateral to the tongue, but as this

moves ventrally with further growth the palatal processes wing medially

and fuse horizontally. The fusion begins along the posterior margin of the

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primitive palate and is complete except for a midline dehiscence at the

future site of the incisive canal. Fusion continues between the palatal

processes and the septum from anterior to the posterior, separating the

nasal and oral cavities and most posteriorly the nasopharynx and the oral

cavity as the palatal process complete the soft palate and uvula. Failure of

fusion between a maxillary process and the corresponding premaxilla

causes a cleft lip. Non fusion between palatal process and nasal septum

results in cleft palate. Failure of the oronasal membrane to rupture results

in choanal atresia.

On either side of the anterior septum, in relation to the paraseptal

Jacobson’s cartilage, an invagination of the ectoderm forms the

vomeronasal organ, which largely disappears in man leaving only a blind

tubular pouch.8

The primitive septum is initially made entirely of cartilage. The

superior part ossifies to form perpendicular plate of ethmoid and the vomer

in the posterioinferior portion, leaving the anteroinferior quadrilateral

cartilaginous plate.

The turbinate bones:

A series of elevations appear on the lateral wall of the nose from

the sixth fetal week which will ultimately form the turbinates. The most

inferior or maxilloturbinal forms the inferior turbinate. The middle, superior

and supreme turbinates result from reduction of the complete

ethmoturbinal system. The primitive nasoturbinal is represented by the

agger nasi region and the uncinate process of the ethmoid.

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The maxillary sinus:

The maxillary sinus appears first and is initially represented as a

depression in the nasal wall below the middle turbinate. The depression

rapidly becomes a groove which grows laterally and invades the body of

the maxilla. The sinus grows in spurts associated with eruption of the

molar teeth and reaches its full size after the time of eruption of the

permanent dentition.

Ethmoid sinuses:

The ethmoidal sinuses are well delineated, fluid filled structures in a

new born child. During fetal development the anterior cells form first,

followed by the posterior cells. The cells grow gradually and are of adult

size by age 12 years. They are not seen on radiographs usually until age

of 1. Septa gradually thin and pneumatisation spreads as the child ages.

Ethmoidal sinuses are the most variable and can often be found above the

orbit, lateral to the sphenoid, into the roof of maxillary sinus, and anteriorly

above the frontal sinus. These cells have been named. A cell above the

orbit i.e. called supraorbital cell and is found in 15% patients. Invasion of

an ethmoidal cell into the floor of frontal sinus is called frontal bulla.

Extension into the middle turbinate is called concha bullosa. Cells in the

roof of maxillary sinus are called Haller’s cells, found in 10% population.

These cells can obstruct the maxillary ostia and narrow the infundibulum

and result in disruption of normal sinus function. Finally a cell which

extends posterolaterally to the sphenoid sinus is called an Onodi cell

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(10%).The common variability of these cells makes preoperative imaging

essential to determine a patient’s individual anatomy.

Frontal sinus:

The frontal sinus develops as an upgrowth from the diverticulum

that is to form the anterior ethmoidal sinus. Growth begins at about sixth

months of intrauterine life, but the developing sinus invades the frontal

bone within the first year after birth. The sinus grows steadily for about 10

years, but shows a more rapid growth at puberty.

Sphenoid sinus:

The sphenoid sinus appears before birth. It is small but definite

cavity at birth. After five years it invades the pre-sphenoid bone and there

are successive periods of rapid growth at about age of 10 years and later

at puberty.

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PHYSIOLOGY OF NOSE AND PARANASAL SINUSES 9

The principle functions of the nose and paranasal sinuses are following-

1. Respiratory channel.

2. Heat exchange

3. Humidification

4. Filtration and ciliary mechanism

5. Nasal resistance

6. Nasal neurovascular reflexes

7. Voice modification

8. Olfaction

The main function of the nose is to purify the inspired air, so as to make it

ideal for gaseous exchange inside the alveoli.

1. Respiratory channel:

The nasal passage constitutes the uppermost part of the conducting

passages along which the ventilation of the pulmonary alveolar surface is

maintained. They serve as a natural airway, distinct from the buccal cavity,

enabling respiration to proceed during mastication.

The tidal air drawn in and forced out through the nose in the

inspiratory and expiratory phases of normal respiration appears to traverse

in the main, fairly well defined pathways through the nasal passages.

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The inspired air entering through the anterior nares is directed

upwards in the narrow stream medial to the middle turbinate and then

downwards and backwards in high parabolic curves. The stream fans out

somewhat as it traverse the posterior choanae. In expiration the air enters

the choana from the nasopharynx and follows the same route, as do the

inspiratory air currents. Anteriorly on meeting the constriction at upper limit

of the vestibule the air current divides. A portion passes through the nostril

and the remainder forms a large central eddy, whirling back through the

inferior meatus and rising to join the main stream from the nasopharynx.

Part of this central eddy passes under the middle turbinate.

2. Heat exchange:

The temperature of the inspired air can vary from -50deg C to

50deg C. The different racial groups have become modified to suit the

local ambient temperatures. The rich vascular arrangements of the nasal

mucosa allow the inspired air to be warmed in its passage through the

nose. The extensive plexus, especially in the inferior turbinates, provide an

efficient radiating system.

3. Humidification:

Adequate saturation of the inspired air is essential for the

maintenance of the efficient functioning and the integrity of the ciliated

epithelium. Moisture is also essential for the proper cleaning of the

pharyngeal mucosa and for the protection from drying of the lining of the

pulmonary alveoli.

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It is generally assumed that the water for humidification comes

directly from the capillaries through the surface epithelium. However the

fluorescent studies showed that except during acute inflammation, little

water comes directly through the surface epithelium. Water comes from

the serous glands, which are extensive throughout the nose. Additional

water is extracted from the expired air, the nasolacrimal duct and the oral

cavity.

The relatively small nasal cavities achieve nearly full saturation of

the inspired air with remarkable efficiency, which becomes 75-95%

saturated in the nose. It has been shown that the daily volume of

secretions and transudate is about 1litre. Some 700 ml are used in

saturating the inspired air; the excess is used in the ciliary cleaning

processes and is finally swallowed.

4. Filtration and ciliary mechanism:

The nose is able to remove particles of 30 micrometer or more from

the inspired air. The inspired air changes direction by 180 degree in

passage through the nose and during this period the velocity decreases

considerably as a consequence of the nasal valve. Turbulence

encountered in the flow increases the deposition of the particles. Fine

particles including bacteria stick to the mucus over the cilia, which is

impelled as a continuous “conveyer belt” into the nasopharynx when they

are swallowed. Lysozymes are bacteriolytic enzymes found in the nasal

mucus and tears. Lactoferrin produced by glandular epithelium is

responsible for removing the heavy metal and by this they prevent the

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growth of the certain bacteria, particularly Staphylococcus and

Pseudomonas. Reflex sneezing helps to expel the inhaled foreign

particles.

A number of different anti-proteases, phospholipids and

triglycerides are present. Their exact function is unknown. All components

of complements have been identified in the nose. It has a variety of

functions including the lysis of microorganisms and enhancement of

neutrophilic functions as well as leucotaxis.

All classes of irnmunoglobulins are found in the nasal secretions.

IgA and IgE have been found in greater quantities than in serum.

5. Nasal resistance:

Narrowest part of the nose is the nasal valve, which physiologically

is less well defined than the anatomical structures, which constitute it. It

comprises the lower edge of the upper lateral cartilage, the anterior end of

the inferior turbinate and the adjacent nasal septum, together with the

surrounding soft tissues. The nasal resistance is high in infants as they are

obligate nose breathers at least initially. Adults breathe preferentially

through the nose at rest even though significant resistance occurs there.

The resistance is important during expiration since the positive pressure is

transmitted to the alveoli and keeps the lungs expanded.

6. Nasal neurovascular reflexes:

The nasal mucous membrane is the specific receptive field for a

large variety of reflex responses affecting particularly the alimentary,

26

cardiovascular and respiratory system. The reflexes may be broadly

divided into two groups, according to the receptors and afferent nerves

involved. They are olfactory and trigeminal. The olfactory group of reflexes

follows stimulation of olfactory receptors and influences chiefly the

secretions of salivary, gastric and pancreatic glands.

The second group includes reflex responses of receptors by touch,

pressure, temperature, pH and chemical irritant. Trigeminal neurons form

the afferent limb of these reflex arcs. These nasal reflexes include, among

others, reflex changes in pulmonary ventilation, changes in laryngeal and

bronchial muscle, and changes in heart rate and blood vessels. The

sneeze is a physiological neuromuscular response to irritation and

autonomic alteration, central nervous system seizures or paroxysmal

psychological response.

7. Voice modification:

The voice is produced by modifying the vibrating column of air from

the Slarynx. The larynx produces the vowel sounds and the pitch of the

voice. High frequency sounds, the consonants, are added by the pharynx,

tongue, lips and teeth. The nose adds quality to this by allowing some air

to escape through it. The sound resonates within the nose and mouth.

8. Olfaction:

Olfactory function of the nose is very complicated. Olfactory

components must contact the nasal mucosa in order to produce a smell

and have to be soluble in water and lipids The human has 200-400 square

27

mm of sensory epithelium with a cellular density of about 5x104 receptor

cells per square mm. Odours are accepted into the water fraction of mucus

and the lipid reacts with the lipid bilayer of the receptor cells at specific

sites. This causes K+ and Cl- to flow out and thereby depolarize the

sensory cells. After a latent period of 400ms, a low compound action

potential may be recorded from the olfactory mucosa which Ottoson called

the electro-olfactogram.

Olfaction is important in regulating behavior in all animals. Smell is

used in four main areas of behavior: the detection and consumption of

food, recognition, territorial marking and sexual behavior.

FUNCTIONS OF PARANASAL SINUSES:

The physiology and function of paranasal sinuses has been the

subject of much research. Multiple theories of function exist. These include

the functions of warming, humidification of air, assisting m regulation of

intranasal pressure and serum gas pressures, contributing to immune

defense, increase mucosal surface area, lightening the skull, giving

resonance to the voice, absorbing shock and contributing to facial growth.

The nose is an amazing humidifier and warmer of air. Even at 7 litres per

minute of air flow the nose has not reached its maximum ability to perform

this function. Nasal humidification has been shown to contribute as much

as 6.9 mmHg on serum p02. Although the nasal mucosa is best adapted

to perform this task, the sinuses contribute to mucosal surface area and

warming ability.

28

Because of the copious mucus production the sinuses contribute

heavily to the immune defense performed by the nose. The nasal and

sinus mucosa is ciliated and functions to move mucus. The thickened

superficial layer of nasal mucus serves to trap bacteria and particulate

matter in a substance rich with immune cells, antibodies and antibacterial

proteins. The underlying layer is much thinner and serves to provide a

thinner substrate in which the cilia are able to beat. Unless obstructed by

disease or anatomical variance, the sinuses move mucus through their

cavities and out of their ostia towards the choanae. The most recent

research on sinus function has focused on molecule nitrous oxide (NO).

Studies have shown that the production of intranasal NO is primarily in the

sinuses. NO has been toxic to bacteria, fungi and viruses at levels as low

as 100ppb.Nasal concentration of this substance can reach upto

30,000ppb. NO has also been shown to increase ciliary motility

29

REVIEW OF LITERATURE

The study of nose is as old as civilization. Prominent structure being

in the middle of nose has acquired a unique status socially, sexually,

aesthetically and physiologically. Various conditions affecting its structure

and function have been documented in Edwin Smith Papyrus in

hieroglyphic script, an Egyptian writing system of the mid 4th Millennium

BC. The major contribution for the complete reconstruction of the nose

originated in India by Shushruta in and around 600 BC. He discovered

“Netiyantra” to examine the nose. Greek physicians, Hippocrates and

Galen, and at the birth of Christianity, Celsus wrote eight books of medical

encyclopedia, which described various conditions affecting nose.

Hippocrates in 460 BC described ‘sponge’ method of nasal polypectomy.

The presence of paranasal sinuses is documented in ancient Egypt.

Sinus surgery probably originated there as instruments were used to

remove brain through the ethmoidal sinuses as a part of mummification

process.

Andreas Vesalius in 1537 described maxillary sinus as an air

containing cavity. Highmore named it as Antrum of Highmore in 1651.

Pere Dionis described first nasal speculum in 1714. A New York surgeon

George Caldwell in 1893 described the procedure of entering the maxillary

sinus through the canine fossa, removing the mucous membrane and

making a permanent opening in the inferior meatus to drain the sinus.

Incidentally another surgeon in France named Henry Luc was also working

on the same operation which then was described as Caldwell Luc

30

operation. The quest to look into the sinuses continued with Wertheim in

1896 designing a “conchoscope” to look deeper into middle meatus.

With better visualization of the nasal cavity, Parson Schaffer in

1912-1923 described the intricate anatomy of the lateral wall of nose and

paranasal sinuses. Harris Mosher emphasized the importance of Agger

nasi cells in frontal sinus surgery.

In the late 20th century, Prof. Messerklinger in 1967 studied and

documented genetically determined pathways of mucociliary mechanism

in all sinuses and any obstruction to its natural drainage was responsible

for continued sinus dysfunction. He emphasized that the anterior ethmoid

and osteomeatal complex was the ‘key’ to chronic sinus disease. This

formed the basis of chronic recurrent sinusitis. This event along with the

nasal endoscopy described by Prof. Draf with the development of fibre

optics and CT imaging heralded a new era, which evolved in functional

endoscopic sinus surgery. Later on Prof. H. Stammberger popularized the

technique and published his experience of functional endoscopic sinus

surgery in 1991.5 This new technology further enhanced the scope of

endoscope being used ‘around and beyond’ the nose.

However certain diseases continue to prove a challenge to

mankind. One such condition is fungal infection. This discussion

emphasizes issues that relate to fungal rhinosinusitis. The American

academy Of Otolaryngology’s task force on rhinosinusitis suggested the

term ‘rhinosinusitis’ more accurately describing the disease process than

the term ‘sinusitis’. As the linings of nose and paranasal sinuses are

31

continuous, inflammatory processes tend to involve both areas to a greater

or lesser extent.

Fungal sinusitis as an entity was described in the late 1700s.10 By

mid-1800 to late 1800s; it was described in both invasive and non-invasive

forms. Non-invasive Aspergillosis of the nose and paranasal sinuses was

first described by Schubert in 1855 and invasive fungal rhinosinusitis was

first reported by Oppe in 1897. It was in1965 when Hora actually put the

whole picture together and described Fungal rhinosinusitis as a spectrum

of disease ranging from non-invasive to invasive. If one looks at the

literature over the history of this disease, it has had some confusing

nomenclature, and up until recent years, it has not really had a standard

nomenclature.

In 1997, deShazo reviewed the literature on fungal rhinosinusitis

and proposed a standard classification by which to look at these cases.

He, as before broke it down into invasive and non-invasive forms. Then he

characterized five major types. The first of the non-invasive forms was

allergic fungal sinusitis as well as sinus fungal ball. Of the invasive forms

the most common form is what he described as acute or fulminant invasive

sinusitis. Then he described chronic invasive fungal rhinosinusitis, and

finally granulomatous invasive fungal rhinosinusitis. Berrylin J. Fergusson

described saprophytic colonisation as a subtype of non-invasive fungal

sinusitis.11

All these manifestations overlap or progress from a non-invasive

form to an invasive form if immunogenic status of the patient changes.

32

This prognosis is less dependent on a particular fungus causing the

infection than the manifestation of fungal infection in the host which is

dependent on immunogenic status of the host.

Overview of vast medical mycology in relation to fungal

rhinosinusitis 12

Fungi are eukaryotes that evolved shortly before plants and

animals. The number of fungal species probably exceeds 50,000, but only

a few hundred species of fungi are implicated in human disease, and 90%

of human infections can be attributed to a few dozen fungi. Although many

cases of fungal rhinosinusitis are caused by species of Aspergillus,

Dematiaceous moulds or Zygomycetes, the range of confirmed and

potential fungal elements is extensive and expanding.

Each fungal cell possesses at least one nucleus and nuclear

membrane, endoplasmic reticulum, mitochondria, and secretory

apparatus. Most fungi are facultative or obligate aerobes. Fungi grow as

yeasts and moulds.

Yeasts are single cells, usually spherical to elliptoid in shape

varying in diameter from 3 to15 microns. Most yeasts reproduce by

budding. Under certain conditions some pathogenic yeasts produce buds

that characteristically fail to detach and become elongated, producing a

chain of elongated yeast cells called pseudohyphae. All fungi have rigid

cell walls that determine their shape. Cell walls are composed of

33

carbohydrate layers and long chains of polysaccharides as well as

glycoproteins and lipids.

Pathobiotic properties of cell walls:

1. Surface components of cell wall mediate attachment of the fungus to

host cells.

2. Cell wall polysaccharides may activate the alternative pathway of

complement cascade to stimulate the inflammatory reaction.

3. Fungal cell wall is degraded poorly by the host and can be detected with

special stains.

4. Cell wall release immunodominant antigens that may elicit cellular

immune responses. In addition to their vegetative growth as yeasts or

moulds, fungi can produce spores to enhance their survival. Spores can

be readily airborne and dispersed, are more resistant to adverse

conditions, and can germinate when conditions for growth are favorable.

Spores can derive from asexual or sexual reproduction, which are called

anamorphic and teleomorphic states, respectively.

The medical fungi produce two types of asexual spores, conidia and

sporangiophores. In the zygomycetes, sporangiophores are produced by

mitotic replication and spore formation within a sac like structure called a

sporangium, which is supported by sporangiophores. The ever changing

classification of fungi is based upon the process of sexual reproduction.

Some fungal genera and species implicated in fungal rhinosinusitis.

34

Category Genera

Zygomycetes Absidia,

Cunninghamella

Mucor Rhizomucor

Rhizopus

Hyaline moulds Aspergillus

Blastomyces dermatitidis

Chrysosorim

Fusaium

Penicillum

Pseudallescheria boydii

Scedosporium

Scopulariopsis

Dematiaceousmoulds Alternaria

Bipolaris

Curvularia

Exserohilum

Cladosporium

Ascomycetous yeasts Candida

Basidiomycetes Coprinus

Cryptococcus neoformans

Schizophyllum

Ustilago

35

Rhinosinusitis follows inhalation of nasal spores into nasal passages. The

outcome of inhaling an innoculum of spores depends upon several factors:

1. The number of spores inhaled.

2. The size of fungal particles.

3. The immunity of the host.

4. The pathobiologic potential or virulence of the particular fungus.

Diagnosis of mycotic infections:

Specimens:

While examining a patient with rhinosinusitis, any exudate, infected

material or necrotic tissue should be rapidly transported to the laboratory

for direct examination and culture. Swabs should be avoided.

Microscopic examination:

The ideal stain for histopathological direct examination is a mixture

of KOH and Calcofluor white.

Histopathological examination of specimens:

Exudates or specimens can be stained with:

Hematoxylin and Eosin (H and E)

Gomori Methenamine Silver (GMS)

Periodic Acid Schiff (PAS)

36

GMS and PAS stains are superior to H & E and stain the cell wall black or

red respectively. The melanin of dematiaceous fungi is often present on H

and E slides. The Fontana Masson melanin stain is useful in differentiating

these fungi from non melanin containing fungi such as Aspergillus.

Culture identification:

The traditional medium is Sabouraud’s agar which contains glucose

and beef extract. Their identification is based upon morphology of their

conidia.PCR methods can be employed to detect various taxa and genera

based upon ribosomal DNA.

Serologv and skin tests:

Precipitins and specific lgG and igE antibodies are detected in

serum by various enzyme immunoassay and radioimmunoassay. The

antibody class and skin tests can help to differentiate among invasive,

non-invasive and allergic fungal rhinosinusitis.

Management of fungal infections:

Various approaches to manage fungal infections include

endoscopic surgery, systemic corticosteroids, topical and systemic

antifungal antibiotics and immunotherapy.

37

ALLERGIC FUNGAL RHINOSINUSITIS 13

It is a term introduced by Robson et al in 1989 to describe a

constellation of unusual findings in a unique group of patients suffering

from chronic sinusitis.14

Epidemiology of Allergic Fungal Rhinosinusitis:

The prevalence of allergic fungal rhinosinusitis in chronic

rhinosinusitis patients who require surgery is between 5% to 10%. Allergic

fungal rhinosinusitis is noted more commonly in a younger group of

patients varying from 23 to 42.4 yrs of age.15,16 Some studies have noted a

fairly equal sex predilection for AFRS whereas Manning and Holeman

noted a male preponderance of 1.6 males per female.16,17 The diseases

seem more common in warmer, humid climate. The first to report the

incidence of AFRS was Katzenstein in 1983 with an incidence of 6.2%

from St.Louis, Missouri, which lies along the central Mississippi river. One

third to one half of AFRS patients have asthma.16,17

Deshpande, Shukla and M V Kirtane found that the incidence of

AFRS of all sinus surgeries in Mumbai in a 4 year study is 8.2% which is

the highest reported incidence in literature.18

Pathophysiology of Allergic Fungal Rhinosinusitis:

Miller demonstrated Type-1 hypersensitivity to Aspergillus

fumigatus in a group of patients with a constellation of symptoms and

findings that can be labelled as AFRS. Members of the dematiaceous

family are actually the most common agents involved in AFRS.

38

Symptoms of AFRS:

The patient typically has a history of nasal polyposis and may have

had previous sinonasal surgery. The incidence of nasal polyposis in AFRS

is almost 100%.15 They may have documented atopic disease. Children

with AFRS commonly have proptosis.1675% patients diagnosed as having

AFRS describe expelling dark coloured rubbery nasal casts.17

Bent and Kuhn diagnostic criteria for AFRS:

1. Type-1 hypersensitivity.

2. Nasal polyps.

3. Characteristic CT scan findings.

4. Positive fungal stain or culture.

5. Allergic mucin with fungal elements and no tissue invasion.

Marple uses the same diagnostic criteria though he excludes the

requirement of fungal culture because a negative culture may be caused

by laboratory inexperience, and a positive culture may represent a

saprophytic growth of fungi.

In actuality an atopic individual who lacks nasal polyps, a

characteristic CT,or positive fungal cultures, but has the characteristic

histopathology of allergic mucin with hyphal elements is still diagnosed as

having AFRS.

Preoperative steroids may reduce the nasal polyps and facilitate the

identification of surgical landmarks, but may obfuscate the diagnosis of

39

AFRS. Graham and Ballas described such a case in which preoperative

high dose steroids resolved the eosinophilic mucin. The pathologists saw

only a matte of fungal hyphae and diagnosed it as a fungal ball. When

steroids were tapered off post operatively, the AFRS recurred and the

diagnosis was confirmed by characteristic histopathology.

Examination of acid mucin by H and E stain reveals eosinophils,

Charcoat laden crystals, and possibly fungal hyphae within a background

of eosinophilic or basophilic mucinous material. The Charcoat laden

crystals are composed of lipophospholipase and range in size from 2 to 60

micrometers. The crystals are depicted especially well with a Brown Brenn

stain.19 GMS stain is typically used to visualize the fungal elements within

the allergic mucin. Fontana masons stain actually may allow the

microscopist to more easily distinguish the dematiaceous fungi from other

septate fungi, as it stains the melanin that is characteristic of the former

group.

AFRS CT scans show characteristic findings:

Central areas of hyperattenuation within the sinus cavity on CT

scan correspond to areas of hypointensity on T-1 weighted MR images

and signal void on T2 weighted MR images.

Central areas of hyperattenuation within the sinus cavity on CT

scan may take on various patterns including a star filled sky, ground glass

or serpiginous pattern. Bony loss is common as the expanding

inflammatory lesion pushes and thins the surrounding bone. The disease

may progress from frontal sinus into the orbit below, or posterior through

40

the posterior table to involve the anterior skull base. Disease may spread

laterally from ethmoid region to erode the lamina papyracea. Although

exposed, the soft tissue barriers of dura or periorbita are not involved by

the fungus.

Role of surgery in management of AFRS: 20

Surgery has been the single invariable component of combination

therapy for AFRS. An aggressive approach initially was adopted because

of perceived risk of fungal infections.

Increased acceptance of the disease as of a specific immunologic

hypersensitivity has led to changes in its management. Radical surgery for

AFRS has given way to more conservative, tissue sparing approaches.

Mabry et al refer to this surgery as conservative21but complete, relying

almost completely upon endoscopic techniques. Nasal polyposis is

inherent to AFRS and can cause distortion of local anatomy and loss of

surgical landmarks.

Aside from these problems, polyps can provide an important

intraoperative role by serving as a marker of the disease. AFRS causes a

relatively consistent configuration of the disease. Because of the non-

invasive nature of the disease, it may be removed in a blunt fashion,

leaving the involved sinus completely lined with intact mucosa.

Preservation of mucosa provides protection of adjacent anatomical

structures, even in the face of large areas of anatomical dehiscence.

41

The next goal of the surgery is to impart permanent drainage and

ventilation to the affected sinuses. Postoperative care begins immediately

following surgery in the form of nasal saline irrigation. Weekly clinical visits

are requested initially to allow regular inspection of operative areas as well

as debridement of crusts and retained fungal debris if necessary. Systemic

corticosteroids are continued postoperatively.

Complications:

In addition to fungal or bacterial seeding, penetration of dura or

periorbita may lead to injury of the structures within it. It can result in

diplopia, blindness, haemorrhage, stroke, intracranial hemorrhage, or CSF

rhinorrhea. Erosion of osseous boundaries may increase the risk of

formation of encephalocele.

Role of steroids, antifungals and immunotherapy in the management

of AFRS: 22

Waxman et al suggested the use of systemic corticosteroids in the

treatment of AFRS23 based on the treatment modalities used in ABPA.

Kuhn and Javer recommend beginning oral prednisolone in a dose of 0.4

mg/kg for 4 days. The dose is then decreased by 0.1 mg/kg/day in cycles

of 4 days until a dose of 20mg/day or 0.2mg/kg/day whichever is greater is

reached. This is continued until the 1 month postoperative visit when it is

adjusted to 0.2mg/kg/day. This dose is then maintained and the patient is

then followed monthly with both nasal endoscopy and total serum IgE

levels. Intranasal steroid spray is simultaneously started in a dose of one

42

spray in each nostril 3 times daily. Endoscopy and total serum IgE levels

are measured monthly for 6 months and then bimonthly for 3 to 5 years.

The adverse effects of systemic steroids:

Accelerated Osteoporosis, Cataracts, Glaucoma and Avascular

necrosis of hip.

Kupferberg and Bent cautioned that systemic corticosteroids should

be weaned aggressively in children with AFRS to minimize possible long

term growth retardation. Topical and systemic antifungal therapy for AFRS

has been studied by Kuhn and colleagues with mixed to poor results.

Mabry and colleagues have made a considerable effort

investigating immunotherapy for AFRS. They have stated that

immunotherapy produced a decreased amount of crusting and polyposis

as well as a reduction in the need of systemic and topical corticosteroids in

these patients.

A retrospective review by Fergusson of 7 patients who received

immunotherapy without adequate surgical and medical management

indicated that 5 patients did not improve or worsened with immunotherapy.

Issues not in favour of immunotherapy are:

It may incite a Gell and Coombs Type-3 Arthus reaction with

immune complex mediated tissue damage. There may be possible

worsening of the disease with introduction of extraneous fungal antigens to

patients with AFRS. Antigens of many common fungal allergens are not

available commercially. Laboratories capable of measuring fungal specific

43

serum IgE levels for all fungi are not available. Immunotherapy may be a

promising direction in which to develop a supplemental treatment option

for surgery and steroid therapy of this difficult disease.

44

FUNGAL BALLS OF THE PARANASAL SINUSES 24

Fungus balls of the paranasal sinuses are composed of matted

fungal hyphae. In the literature the term mycetoma is frequently used to

describe these paranasal sinuses fungal ball. In older literature the term

Aspergilloma or Aspergillosis was often used for paranasal sinus Fungus

balls even if fungal cultures are not performed or fail to grow. In 1893

Mackenzie reported the first case published in English of a non-invasive

fungal sinusitis. deShazo and colleagues in the review of English literature

cases through 1996 identified 20 patients in 11 reports that met their

criteria for paranasal sinus Fungus balls and added 5 cases of their own.25

Subsequently large series from Mayo clinic with 29 cases26 and France

with 109 cases27 added to the clinical characterization of this fungal

manifestation.

Epidemiology:

Older individuals appear more susceptible. The average age

reported in an American retrospective series of 29 cases was 64 years,

ranging from 28 to 86 years. A comprehensive review by deShazo and

Klossek also showed a similar age range with the youngest reported being

18 years.25,27 No pediatric cases have been reported. In all English

language literature available for review, there is consistently a female

preponderance of about 64%.25,26

45

Clinical presentation:

The common symptoms include nasal obstruction, purulent nasal

discharge, cacosmia or facial pain. Unusual symptoms include onset of

seizures, epistaxis, proptosis, fever, cough and blurred vision. Ten percent

of the patients have polyps.27

Radiographs:

The most commonly infested sinus is the maxillary followed by the

sphenoid. 102 of 109 cases (94%) had only a single sinus involved.27A

radiographic imaging most commonly shows complete or subtotal

opacification of the involved sinuses. On sinus CT, 97 of 109 cases show

heterogenous opacity. Upto half the cases demonstrate radiodensities

within the central portion of the soft tissue mass.27These represent

calcifications or dense hyphae. Occasionally a mucocele or foreign body

or even an antrochoanal polyp may be seen.

Histopathology:

Fungus balls are extra mucosal fungal infestations. No invasion is

present. Granulomatous reaction is absent. A tangled mat of hyphae is

present on histopathology. Grossly the fungus is gritty, occasionally

cheesy, often fragmenting easily into clay like particles. Colour can range

from brown to black to green or yellow.

46

Fungal cultures:

Fungi reported to cause fungal balls include A.fumigatus, flavus,

Alternaria sp., and P.boydii. Failure ofthe fungus to grow on fungal cultures

is common with only 23 to 50% of cultures resulting in fungal growth.

Immunology:

Immunologically most patients appear to be normal. If

immunosuppression develops these patients are at high risk for

developing invasive fungal rhinosinusitis.

Pathogenesis:

The most likely cause of fungal balls is the persistence of fungal

spores within the nasal cavity, or entrance of the fungal spores into the

maxillary or the other sinus through accessory ostia, and subsequent

germination and growth.

Treatment:

The treatment of paranasal sinus fungal balls is surgical removal. In

the past these patients were approached externally. This has been largely

replaced with endoscopic techniques. No recurrences were found in

patients treated with Caldwel Luc technique in the Mayo clinic series.26

47

SAPROPHYTIC FUNGAL INFESTATION 11

Saprophytic fungal infestation refers to the presence of fungal

spores on mucous crusts within the nose and paranasal sinuses. The

incidence of this phenomenon is unknown. It is frequently seen upon

endoscopic examination of the nose and the paranasal sinuses. It may be

more frequent in patients who have undergone previous endoscopic sinus

surgery, because such surgery may disrupt the mucociliary transport

pathways and allow the formation of crusts upon which fungus can grow.

Histopahologically, if the mucocrusts were sampled, the hyphae could be

seen. Culture would reveal a variety of fungi. This if left undisturbed would

become a fungus ball. At this stage, the only therapy required is

endoscopic cleaning. If fungal mucocrusts continue to accumulate, instruct

the patient in mechanical cleaning with saline irrigation using a water pilk

or a baby bulb syringe on a weekly basis to resolve the problem.

Saprophytic fungal colonization is defined as the visible growth of fungus

within the nasal cavity of an asymptomatic individual and does not refer to

fungi that are not visibly growing but present by culture alone. This is

important because fungus can be cultured from virtually any individual’s

nose, if one uses elaborate washes and culturing methods.

48

ACUTE FULMINANT INVASIVE FUNGAL SINUSITIS 28

Acute fulminant invasive fungal rhinosinusitis is a disorder

characterized by mycotic infiltration of the mucosa of the nasal cavity and

paranasal sinuses. In the absence of treatment the disease is rapidly fatal

in 50% to 80% of the orbit an of the patients secondary to the invasion of

the orbit and intracranial cavity.29,30,31The primary risk factor for the

development of acute fulminant invasive fungal rhinosinusitis is an

immunocompromised state. The disorder always occurs in patients with an

impaired neutrophilic response secondary to disorders such as

Poorly controlled Type 1 diabetes mellitus

AIDS

Hemochromatosis

Aplastic anemia

Iatrogenic immunosuppression

Organ transplantation

Hematologic malignancy.

Clinical features:

The most common symptom in upto 90% of patients is fever of

unknown origin that has not responded to 48 hrs of broad spectrum

intravenous antibiotics.30 Absence of fever does not rule out the disorder

especially in patients with localizing symptoms such as facial or periorbital

pain, nasal congestion and rhinorrhea and headache which are invariably

present in 20% to 60% of patients.29,30,32 Late signs and symptoms include

49

loss of visual acuity, opthalmoplegia, proptosis, and change in mental

status, focal neurological signs and seizures.

On a thorough rigid endoscopic nasal examination, the most

consistent physical finding is an alteration in appearance of the nasal

mucosa. Mucosal discoloration is variable and may be grey, green white or

black. White discoloration of the mucosa indicates tissue ischaemia

secondary to angiocentric invasion whereas black discoloration is a late

finding signifying tissue necrosis.

A thorough head and neck examination is also mandatory. The

patient’s level of consciousness and awareness to person, place and time

provides the rough evaluation of the central nervous system function. The

face is palpated tor paranasal sinus tenderness. A full cranial nerve

evaluation, with particular attention to facial sensation, extraocular muscle

function, afferent pupillary reflex and visual acuity is performed.

Radiology:

CT of the paranasal sinuses:

Fine cut (1 mm) CTscan of the paranasal sinuses should be

obtained in both the coronal and axial views in order to maximize

anatomical details. CT findings in invasive fungal rhinosinusitis are non-

specific and do not correlate well with surgical and pathologic findings. The

CT scan can document the presence of sinusitis and demonstrate which

sinuses are to be addressed surgically. A scan can demonstrate individual

variations in bony architecture, which may prevent potential surgical

50

complications. This ability of the scan makes it the imaging study of

choice. CT scans may have findings suggestive of an invasive sinonasal

disorder.

MR imaging is however superior to CT in delineating intracranial

extent of the disease.29,31 A mortality rate of 100% has been demonstrated

in patients with intracranial involvement.29,30 MR imaging may prevent

unnecessary procedures in patients who are unlikely to benefit from

surgery.

Diagnosis:

Histopathological evaluation of tissue biopsies is required to confirm

the diagnosis of invasive fungal rhinosinusitis. Fungal disease is

determined to be invasive if it meets the following criteria on

histopathological examination:

1) Hyphal forms within the submucosa with or without angiocentric

invasion.

2) Tissue necrosis with minimal host inflammatory cell infiltration.

Ideally tissues should be sent for frozen and permanent sections.

Permanent sections with GMS staining confirm the diagnosis and provide

important morphologic information for determining the fungal species. The

most common site of invasion is the middle turbinate in approximately two-

third of the patients.28

Treatment:

51

Mainstay of treatment continues to be a combination of antifungal

antibiotics and aggressive surgical debridement. Surgical approach for

invasive fungal rhinosinusitis has been changed over years from radical

surgeries to endoscopic sinus debridement. Clear bleeding margins should

be achieved during endoscopic sinus debridement. The patient should be

scheduled for a second look procedure in 48 to 72 hours if there is

concern of residual disease in the sinonasal cavity.

Surgery does not prolong survival in neutropenic patients who do

not recover their white blood cell counts.29,30 Granulocyte colony

stimulating factor has been shown to be efficacious for promoting bone

marrow recovery in neutropenic patients. These patients are more likely to

become disease survivors. They should continue to receive weekly nasal

endoscopy until reversal of neutropenia, and once a month for 6 months

thereafter.

Role of antifungals in the treatment of acute invasive fungal

sinusitis: 33

It was discovered by Gold and coworkers who were studying the

strains of Streptomyces nodosus, an aerobic actinomycetes, obtained from

the Orinoko river valley of Venezuela.34 In 1958, Chick described the

effectiveness of Amphotericin against Rhizopus infections in rabbits and

rats.32In 1961, Gass described the first human survival treated with this

drug.

52

Since the sixties, surgical treatment combined with Amphotericin B

has become the mainstay of therapy.

Andrew Blitzer et al in 1980 in the study of 9 cases of sinonasal

infection had shown that with surgical debridement or radical resection

survival rate is 78% as compared to 57% with medical line of

management.35 Analysis of patients having combined Amphotericin B and

surgery showed an overall survival of 81%. Amphotericin B remains the

standard drug for most life threatening systemic fungal infections. It is a

polyene macrolide. Its antifungal activity is caused by its ability to bind

preferentially to ergosterol, a major component of fungal cell membrane.

Cell membrane permeability is then increased following attachment of this

lipophilic structure to the fungal cell wall, with leakage of intracellular

components and ultimately cell death.

Unfortunately, Amphotericin B also binds to a lesser degree to

cholesterol in mammalian cell membranes, which probably accounts for its

toxic effects on human cells.

Intravenous doses in the range of 0.25 to 1 mg/kg once daily in 5%

Dextrose solutions usually are recommended. Maximum daily doses of 1.2

mg/kg/day in adult and 1.5m/ kg/day in children are generally are reserved

for serious invasive mycoses.36,37

Hazards of Amphotericin B:

53

Infusion related reactions: chills, rigors, fever, headaches, nausea and

generalized aches. Premedication with acetaminophen, diphenhydramine,

aspirin or ibuprofen may help diminish this reaction.

Nephrotoxicity may occur in upto 80% of patients receiving

Amphotericin B therapy. It is manifested by azotemia, electrolyte wasting

(Mg and K), and a decrease in urinary concentrating ability. Patients

receiving a total dose of 4 to 5grams of Amphotericin B may have

permanent renal impairment. An approach to minimize nephrotoxicity

includes sodium supplementation to maintain intravascular volume and

inhibit tubuloglomerular feedback system.

Lipid based combinations of Amphotericin B:

Recently lipid based formulations of Amphotericin B have been

added to the armamentarium of antifungal agents. Amphotericin B lipid

complex, Amphotericin B cholesterol complex and liposomal Amphotericin

B use a variety of lipid carriers.37,38

The pharmacodynamics of Lipid based combinations of

Amphotericin B differs significantly from that of Amphotericin B

deoxycholate. They are preferentially delivered to reticuloendothelial

system such as the liver and the spleen.37,38 Dose for liposomal

Amphotericin B is 1 to 5 mg/kg. Their use is associated with fewer

breakthrough fungal infections and less infusion related toxicity and

nephrotoxicity.

54

Future directions in antifungal therapy:

In developing new agents, the challenge remains in targeting

compounds that are effective in killing the fungal organism, yet limit the

toxicity to human cells.

Voriconazole is a new triazole and a derivative of Fluconazole.

Voriconazole has demonstrated two to eight-fold more activity against

C.crusei and C.glabrata strains than itraconazole. Other fungal pathogens

in which Voriconazole has demonstrated highly potent in vitro activity are

Aspergillus species, C.neoformans, C.immitis, H.capsulatum.

Studies evaluating the pharmacokinetics of Voriconazole have

demonstrated a relatively high (90%) bioavailability and a mean half life of

6 hours. Like Fluconazole, Voriconazole is metabolized by the hepatic p-

450 enzymes. It is in clinical trial with oral and intravenous preparations.

Clinical trials till date have indicated that Voriconazole is a

promising drug against acute and chronic Aspergillosis. In the setting of

invasive Aspergillosis intravenous doses of 6mg/kg every 12hrs for two

doses, then 3 mg/kg every 12 hrs for upto 30 days has been studied. This

regimen was followed by the course of oral therapy 200mg twice daily to

complete a total of 24 weeks. Side effects have been very limited and

include mild elevations in liver function tests and transient but reversible

visual impairment.

MUCORMYCOSIS 11

55

Upper airway mucormycosis was first described in 1885 by Paltauf

who coined the term mycosis mucorina, which subsequently became

mucormycosis.39In 1943 the more typical findings of advanced rhino-

cerebral mucormycosis, proptosis and opthalmoplegia were reported in a

series of three fatal cases in patients with diabetic ketoacidosis by Gregory

et al.40

In 1955 the first cure of mucormycosis was shown by Harris41 with

increasing recognition of the typical features of mucormycosis and the

development of Amphotericin B in 1956 the universal mortality of the

disease has been decreased dramatically. In diabetic patients the

survivorship ranges from 60% to 90%, whereas in leukemic patients and

those in whom the source of immunocompromise is not easily reversible,

survivorship is 20% to 50%.35,42

Taxonomy:

Mucormycosis is a term to refer to any fungal infections of the order

Mucorales, which belongs to the class Zygomycetes. Rhizopus oryzae is

the prominent pathogen that accounts for 60% of all forms of

mucormycosis and 90% of rhinocerebral cases of

mucormycosis.43,44Apohycomyces elegans is the most recently recognized

agent in immunocompromised patients.11 Assessment of the exact species

is limited by lack of fungal culture information in over half of reported

cases. Regardless of the agent, the clinical presentation & management

are identical.

Important members of the class Zygomycetes are:

56

CLASS ORDER FAMILY GENUS SPECIES

Zygomycetes

Mucorales

Mucoraceae

Absidia

Mucor

Rhizomucor

Rhizopus

Oryzae

Epidemiology and pathogenesis

Diabetics in ketoacidocis are classically affected. In the largest single

series to date of 126 patients with rhino-cerebral mucormycosis, 70% were

diabetic. Rhizopus has an active ketone reductase system and thrives in

high glucose and acidotic conditions.35 Diabetics also have decreased

phagocytic activity because of an impaired glutathione pathway. Normal

serum inhibits Rhizopus growth, whereas serum from patients in diabetic

ketoacidocis stimulates growth.

57

Other risk factors include neutropenia, systemic steroids, protein

calorie malnutrition, solid organ and bone marrow transplant patients,

immunodeficiency, leukemia, and intravenous drug abusers who may

inject spores of Mucorales with their drugs and present with space

occupying lesions of the central nervous system. The relative infrequency

of mucormycosis, in patients with AIDS probably reflects the ability of

neutrophils to prevent growth of the fungus.11 Patients reported infected

with rhino-cerebral mucormycosis range in age from 16 days to 75 years.

At least 14 cases of mucormycosis involving the paranasal sinuses have

occurred in patients without any predisposing factors.

Clinical features:

Depending upon the degree of immunocompromise, the disease

process can be indolent or fulminant. Yohia and colleagues reviewed 208

cases of rhino-orbito-cerebral mucormycosis from the literature between

1970 and 1993.45114 cases from their literature review and experience

were used to provide an estimate of the relative frequency of signs and

symptoms that occur within 72 hours of first symptom.

The leading symptom is fever, which occurred in less than half of

the individuals, followed by nasal ulceration and necrosis, periorbital or

facial swelling, or decreased vision; each occurred in approximately one-

third of cases. An elevated white blood cell count is an early sign in less

than 20% of reported cases. Ultimately, 80% of patients developed a

necrotic lesion on either the nasal or oral mucosa. Facial numbness was

58

reported as an early symptom in only 7% of cases, which is an under

representation of an early symptom that is not usually assessed.

Yohia and colleagues also correlated survival relative to ophthalmic

signs and symptoms and non-ophthalmic signs and symptoms. Only a

third of patients who developed periorbital necrosis and 40% of the

cavernous sinus thrombosis patients have survived. Over half of the

patients with visual impairment or ophthalmoplegia however survived. 72%

of the patients with facial numbness survived. Low survivorship is seen

with hemiplegia (28%), facial necrosis (31%), mental changes (32%) and

fever (41 %). Yohia also found a decline in the survival when the interval to

treatment was greater than 6 days.46

Histopathology:

A presumptive diagnosis of mucormycosis can be made

histopathologically based on the broad ribbon-like hyphae, 10 to 20

microns across, haphazardly branched, and absence or paucity of hyphal

septations. The etiological agents of mucomycosis are readily stained with

hematoxyline and eosin stain and special fungal stains such as GMS.

Once invasive, the organism shows a markedly predilection for

vascular invasion. The propensity of these fungi to invade arteries and

arterioles contributes to an ischemic and acidotic environment, which

stimulates further growth.

59

Radiographs:

In early disease radiographs may be normal. As invasion continues,

one sees the typical findings of early infectious rhinosinusitis.

Only late in progression of the disease, bony erosion is appreciated.

Treatment:

Mainstays for treatment of mucormycosis of the paranasal sinuses

are reversal of immunocompromise, systemic Amphotericin B, and

surgical debridement.

Hyperbaric oxygen therapy is theoretically attractive in treating this

disease because it reverses the ischaemic acidotic conditions that

perpetuate fungal growth. There are no controlled studies regarding its

use. Hyperbaric oxygen treatments are usually given at two atmospheres

for 1 hour on a daily basis upto 30 treatments.

60

CHRONIC INVASIVE FUNGAL SINUSITIS:

Berrylin J Fergusson defines chronic invasive fungal sinusitis as

invasive fungal rhinosinusitis of greater than four weeks duration in which

vascular invasion is minimal or absent.47

deShazo et al has subdivided chronic invasive fungal sinusitis into

cases with granulomatous and non-granulomatous histopathology. But no

difference in prognosis or therapy is yet apparent based on his distinction.

The disease is characterized by a prolonged clinical course with slow

disease progression, sinusitis on radiological imaging, and

histopathological evidence of hyphal forms within sinus mucosa,

submucosa, blood vessels and bone.

Clinical features:

Chronic invasive fungal sinusitis occurs in healthy individuals,

though many have a history of chronic rhinosinusitis, upper airway

allergies, or nasal polyposis. Symptoms directly related to the invasive

disease may take months or years to appear and may only develop once

the orbit or skullbase are involved. Erosion into the orbit from the

paranasalsinuses may produce proptosis. Invasion of the maxillary floor

may produce palatal erosion. Erosion of the cribriform plate may produce

chronic headache, seizures, decreased mental status, or focal

neurological findings. Extension through the sphenoid sinus may lead to

orbital apex syndrome or cavernous sinus syndrome. Extension in to the

pterygopalatine fossa may cause cranial nerve deficits. Some catastrophic

61

complications may occur such as mycotic aneurysm, internal carotid artery

rupture, and cavernous sinus thrombosis.

On intranasal examination, severe nasal congestion and polypoidal

mucosa may be noted. There may be a soft tissue mass that can be either

mucosally covered or ulcerated with overlying debris or dried secretions.

Diagnostic Imaging:

A sinus CT scan is an appropriate initial step in the evaluation of

suspected fungal rhinosinusitis. Mucosal thickening may be noted. Focal

or diffuse areas of hyper attenuation within a sinus are a clue to fungal

colonization, thick mucin plugs, infection, or Allergic fungal sinusits. Soft

tissue infiltration of peri-antral fat planes around the maxillary sinus

provides early evidence of invasive fungal rhinosinusitis in the appropriate

clinical setting. MR imaging is useful for assessing the dural involvement

and the intradural extension of the disease. The ultimate distinction

between invasive and non-invasive fungal rhinosinusitis and neoplasm is

best made histologically.

Although Aspergillus species were originally identified as the

causative organism of chronic invasive fungal rhinosinusitis, it is now

recognised that chronic invasive fungal rhinosinusitis can be caused by a

variety of organisms. At least 23 different species have been reported in all

types of fungal rhinosinusitis. Chronic invasive fungal rhinosinusitis has

specifically been associated with Mucor, Alternaria, Curvularia, Bipolaris,

Candida, Drechslera, Sporothrix schenckii, and Pseudallescheria boydii.

62

Pathophysiology:

Most patients with chronic invasive fungal rhinosinusitis are

immunologically intact. Chakrabarty showed that in patients with

Aspergillus causing invasive disease, only 29% patients with

granulomatous type disease had cutaneous Type 4 hypersensitivity to

aspergillus antigen (delayed skin reaction), whereas none of the non-

granulomatous patients showed Type 4 reactions.48deShazo has reported

that al cases of non-granulomatous chronic invasive fungal rhinosinusitis

occurred in patients with diabetes.1Many of the organisms that cause

chronic invasive fungal rhinosinusitis were previously identified as

saprophytic organisms. The specific virulence factors that are responsible

for the development of invasive disease in most species have not been

completely elucidated.

Sandison speculated that a hot, dry, warm climate with nasal

obstruction is responsible for aspergillus infection, and A. flavus seems

more common in the environment of Northern Sudan. Others propose

mechanical obstruction of the natural sinus ostia as a result of

inflammation, allergic rhinitis, nasal polyposis, septal deviation, or chronic

sinusitis as the ultimate predisposing factor. Milosev believed that

anaerobic conditions in the sinus because of repeated inflammation or

polyps predisposed to invasive fungal disease.

Pathology:

Veress et al described the gross appearance of granulomatous

chronic invasive fungal rhinosinusitis as firm, hard, rubbery, fibrous,

63

grayish-white masses with an irregular surface.49 Periarterial inflammation

without direct involvement of fungal elements and no true vascular

invasion were noted. They described three variants: proliferative

(granulomatous pseudotubercles in a fibrous tissue stroma), exudative-

necrotizing (with prominent foci of necrosis), and a mixed form. deShazo

typified granulomatous chronic invasive fungal rhinosinusitis as

granulomas composed of eosinophilic material surrounded by fungus,

giant cells and palisading nuclei, variable numbers of lymphocytes and

plasma cells.1 Non-granulomatous chronic invasive fungal rhinosinusitis

was characterized by tissue necrosis with little inflammatory infiltrate and

dense hyphal accumulation resembling a fungal ball (mycetoma). The

fungi in this form may breach mucosal barriers to invade blood vessels or

simply cause an arteritis without vascular invasion, although both

granulomatous and non-granulomatous forms may result in tissue

necrosis.

Treatment:

Most published cases have been treated with a combination of

surgery and antifungal chemotherapy. Much of the advice previously

published for treating sinus aspergillosis is no longer valid because of lack

in specificity of diagnosis. Some suggest that cure can be achieved with

surgical debridement alone or with a combination of debridement followed

by a short course of antifungal therapy. deShazo feels that non-

granulomatous chronic invasive fungal rhinosinusitis should be treated

with an aggressive surgical approach similar to that for fulminant invasive

fungal rhinosinusitis.

64

Washburn has noted that chronic invasive fungal rhinosinusitis

frequently recurs despite surgical debridement and recommends a

prolonged course of Amphotericin B exceeding 2 gm for adults after

surgery.50 In contrast, deShazo feels that granulomatous invasive fungal

rhinosinusitis responds well to surgery alone without need of antifungal

antibiotic therapy. Zieske, in a mixed series of patients, some of whom

today would be classified as having AFS, recommended that for patients

with histologic invasion and extension beyond sinus confines, sinus

debridement and wide aeration should be followed by 1 to 2 grams of

amphotericin B. If persistent or recurrent disease develops, Itraconazole

200 to 400mg per day for 6 to 12 months may be added. Fungal cultures

are necessary because not all fungi are sensitive to amphotericin B or

itraconazole.45

PREVENTION AND PROPHYLAXIS OF INVASIVE FUNGAL SINUSITIS

IN THE IMMUNOCOMPROMISED PATIENTS 51

Prevention by decreasing environmental exposure:

65

These interventions apply to Aspergillus as well as other

filamentous fungi and have been described as being useful most often in

the setting of allogenic bone marrow transplantation and prolonged

granulocytopenia after chemotherapy for leukemia.

Because many patients are hospitalized during the period when

they are at highest risk of infection, nosocomial acquisition of aspergillosis

has been described many times. Hospital associated outbreaks are

usually related to contamination of the ventilation system supplying the

hematology or the transplant unit or passive transmission of large number

of conidia aerosolised into the ventilation system by demolition or

construction projects. Other sources of Aspergillus and filamentous fungi

in the hospital include potted plants, food stuffs, and fire proofing and

insulating materials.

All hospitals caring for immunosuppressed patients should establish

general policies to decrease the fungal burden to which patients are

exposed. Potted plants and flowers should not be allowed on the unit and

ground pepper should not be used as seasoning. Regular cleaning of air

ducts and maneuvers to discourage birds from nesting on seels and roofs

should be carried out. Patients at greatest risk should minimize time spent

outside their room; when they do leave many centres advocate use of a

mask.

The ideal environment in terms of decreasing the number of conidia

to which patients are exposed, is a specially constructed room that

incorporates laminar air flow and high efficiency particulate air filtration

66

(HEPA).These measures diminish the airborne filamentous fungus burden

and have been shown to decrease infections in neutropenic patients.

Prevention with prophylactic antifungal drugs:

Several principals require consideration when selecting an effective

prophylactic regimen.

Targeting pathogens most likely to cause the infection.

Identifying subsets of patients at highest risk for fungal sinusitis.

Limiting prophylaxis to the period of time when risk is highest.

Choosing a safe, well tolerated drug with minimal toxicity and

interactions.

Monitoring patients for drug related side effects and development of

resistance to the agents.

Evaluating the cost of regimen in relation to its efficacy.

Because Aspergillus species are the most common cause of invasive

fungal sinusitis in immunocompromised patients, drugs active against this

pathogen should be an integral part of any successful regimen. Invasive

Candida infection is rare and should not be a target of prophylaxis.

Infections caused by Zygomycetes, Alternaria, Bipolaris and the others are

uncommon enough that antifungal prophylaxis is not feasible.

Prophylaxis should be limited to patients likely to develop infection

and should be given only during the period of highest risk. If all

immunocompromised patients received prophylaxis against filamentous

fungi, drug related side effects and the development of resistance to

67

antifungal agents would undoubtedly overshadow the benefit seen for a

few individuals with neutropenia.

.MATERIALS AND METHODS

A prospective study of 30 cases of fungal rhinosinusitis was carried

from July 2009 to October 2011.

68

A detailed study of history and clinical presentation, thorough

clinical examination, investigations including CT PNS was done. Following

diagnostic endoscopy, patients were subjected to the appropriate surgery.

Surgical specimens were sent for KOH mount, fungal culture and

histopathological examination. Patients were treated with appropriate

antifungals, topical or systemic steroids accordingly. A record of follow up

of these patients weekly for 1 month, fortnightly for 3 months, and monthly

for 6 months was also kept.

CASE RECORD FORM

MANAGEMENT OF FUNGAL RHINOSINUSITIS IN A TERTIARY

HEALTHE CARE CENTRE.

Name: IPD No:

Age: Address:

Sex:

Chief complaints:

Nasal symptoms:

• Excessive sneezing

Occasional/Cascade

• Nasal blockage

Duration, Onset: Days/ Weeks /Months /Years

69

Laterality: unilateral/bilateral

Latency: constant/intermittent

Severity

Character: during inspiration/expiration

Aggravating/Ameliorating factors:

• Nasal discharge:

Duration/ Onset: Days/Weeks /Months /Years

Duration/ Onset: Days/Weeks /Months /Years

Laterality:Unilateral/Bilateral

Latency: constant/intermittent

Severity

Character: Watery/ Mucoid/ Mucopurulent/ Purulent/ Blood stained

Nasal mass

Duration/ Onset: Days/Weeks /Months /Years

Duration/ Onset: Days/Weeks /Months /Years

Laterality: Unilateral/Bilateral

Related nasal obstruction

Enlarging/ Static/ Regressing

Associated symptoms:

70

• Facial pain:

Onset/ Duration

Spontaneous/Induced

Aggravating/Ameliorating factors

Associated fever

Nature of pain: Stabbing/ cutting/dull aching

Spread

Postural/ Diurnal variation

Dental hygiene

• Facial swelling;

Duration/ Onset: Days/ Weeks/ Months /Years

Laterality: Unilateral/ bilateral

Static / progressive/ regressive

H/O trauma

• Disturbances in smell

• Nasal crusting:

Duration/ Onset: Days/ Weeks /Months /Years

Laterality: Unilateral/ Bilateral

Type/colour

71

Epistaxis:

Fresh /clotted/ blood stained discharge

Amount of blood

H/O Trauma

H/O Taking drugs

H/O Bleeding from any site

H/O Bleeding in family

• Postnasal drip

Associated symptoms:

Disturbances in vision

• Drooping of eyelid

• Headache

• Deviation of angle of mouth

Past history

• H/O similar illness in past

• H/O any childhood illness

• H/O any exposure

• H/O major illness in past

• H/O surgery in past

72

Personal history:

Family history:

General examination:

Level of consciousness: Orientation:

Built: Temperature:

PR RR BP

Pallor/ icterus/ cyanosis /clubbing/ edema/ Lymphadenopathy

ENT examination:

Nose:

Inspection: deformity/swelling of nose or face

Palpation:

Anterior Rhinoscopy:

Vestibule: Septum:

Spur: Turbinates:

Nasal mucosa: Nasal secretions:

Crusts: Type/ Colour Nasal mass:

Posterior Rhinosopy:

73

PNS examination:

Sinus tenderness: maxillary/ frontal/ ethmoidal

Cold spatula test:

Oral cavity and throat examination:

Oral hygiene: Oral mucosa;

Tongue: Teeth:

Hard palate:

Posterior pharyngeal wall:

Indirect Laryngoscopy:

Ear examination:

Neck examination:

Ophthalmic examination:

Lids: Sclera:

Conjunctiva: Cornea:

Iris: Pupil:

Proptosis: mild/moderate/severe

Vision: normal/decreased

Fundus Exam:

CNS examination:

74

Higher functions:

Consciousness/behaviour/intelligence

Memory/speech

Signs of cranial nerve involvement:

Pupillary changes/ visual disturbances

Corneal/conjunctival reflex

Sensation over face

Deviation of angle of mouth

Difficulty in eye closure

Motor system:

Nutrition /tone/ power/ataxia/involuntary movements

Sensory system:

Touch/pain/temperature

Signs of raised ICT:

Bradycardia/ neck rigidity/ Kernig’s sign/ Brudzinski’s sign/

papilloedema

Respiratory system:

Gastrointestinal system:

Investigations:

75

Haemogram: BSL: Serum electrolytes:

LFT: RFT: Urine:

Radiological investigations:

X ray PNS Caldwell’s and Water’s view:

CT-PNS:

MRI-PNS:

Nasal endoscopy:

Discharge/crusts/eschar/fungal balls

Microbiological examination:

KOH Mount

Fungal culture:

Histopathological examination:

Diagnosis:

Treatment:

Medical

Surgical:

Intra-operative findings:

Follow up after discharge:1 Month/3month/6months

76

OBSERVATIONS AND RESULTS

TABLE NO. 1: DIAGNOSTIC ANALYSIS

Diagnostic Analysis No. of Percentage

77

cases out of 30

NON-INVASIVE FUNGAL

RHINOSINUSITIS

Allergic fungal rhinosinusitis 16 53.34%Fungal Ball 2 6.67%

Saprophytic colonisation 1 3.33%

INVASIVE FUNGAL RHINOSINUSITIS

Acute fulminant invasive fungal rhinosinusitis

9 30%

Chronic invasive fungal rhinosinusitis

1 3.33%

Chronic Granulomatous invasive fungal rhinosinusitis

1 3.33%

Allergic fungal rhinosinusitis

Fungal Ball

Saprophytic colonisation

Acute fulminant invasive fungal rhinosinusitis

Chronic invasive fungal rhinosinusitis

Chronic Granulomatous invasive fungal rhinosinusitis

16

2

1

1

1

1

Chart no .1 :Diagnostic anal-ysis

no.of cases

TABLE NO. 2: AGE DISTRIBUTION

Age (years) No. of cases with non-invasive

fungal sinusitis

No. of cases with invasive fungal

sinusitis

Total no. of cases Percentage

78

10-20 4 0 4 13.33%21-30 5 0 5 16.67%31-40 3 1 4 13.33%41-50 5 3 8 26.67%51-60 1 4 5 16.67%61-70 1 3 4 13.33%

10 to 20 21 to 30 31 to 40 41 to 50 51 to 60 61 to 700

1

2

3

4

5

6

7

8

9

4

5

3

5

1 1

0

0

1

3

4

3

Non-invasive fungal rhinosinusitis Invasive fungal sinusitis

79

Chart no. 2: Age Distribution

TABLE NO. 3: SEX DISTRIBUTION

Sex No. of cases with non-

invasive fungal sinusitis

No. of cases with invasive

fungal sinusitis

Total no. of cases

Percentage

Male 8 8 16 53.33 %Female 11 3 14 46.66 %

Non-invasive fungal sinusitis Invasive fungal sinusitis0

1

2

3

4

5

6

7

Chart no. 3: Sex Distribution

Females

Males

TABLE NO. 4: PRESENTING SYMPTOMS

80

Symptom No. of cases with non-

invasive fungal

sinusitis

Percentage out of 19

No. of cases with invasive fungal

sinusitis

Percentage out of 11

Total no. of cases

Percentage out of 30

Excessive sneezing

12 63.15 0 0 12 40

Nasal obstruction

19 100 10 90.90 29 96.67

Nasal discharge

10 52.63 5 45.45 15 50

Facial pain 5 26.31 5 45.45 10 33.33Headache 14 73.68 7 63.63 21 70

Fever 0 0 6 54.54 6 20Facial

swelling0 0 8 72.72 8 26.67

Deviation of angle of mouth

0 0 4 36.36 4 13.33

Diminution of vision

0 0 7 63.63 7 23.33

Paraesthesia 0 0 8 72.72 8 26.67

Excessive sneezing

Nasal obstruction

Nasal discharge 3

Facial pain

Headache

Fever

Facial swelling

Deviation of angle of mouth

Diminution of vision

Paraesthesia

0 2 4 6 8 10 12 14 16 18 20

0

10

5

5

7

6

8

4

7

8

Chart no. 4: Presenting Symptoms

Invasive fungal sinusitisNon-invasive fungal sinusitis

81

TABLE NO. 5: SIGNS

Signs No. of cases with non-

invasive

fungal sinusiti

s

Percentage out of

19

No. of cases with

invasive

fungal sinusiti

s

Percentage out of

11

Total no. of

cases

Percentage out of

30

Nasal polyposis

12 63.15 0 0 12 40

Proptosis 1 5.26 7 63.63 8 26.67Opthalmople

gia0 0 7 63.63 7 23.33

Ptosis 0 0 7 63.63 7 23.33Palatal erosion

0 0 3 27.27 3 10

Nasal polyposis

Proptosis

Opthalmoplegia

Ptosis

Palatal erosion

12

1

0

0

0

0

7

7

7

3

Chart no. 5: SignsInvasive fungal sinusitis Non-invasive fungal sinusitis

TABLE NO. 6: ASSOCIATED DISEASES

82

Associated diseases

No. of cases with non-

invasive

fungal sinusiti

s

Percentage out of

19

No. of cases with

invasive

fungal sinusiti

s

Percentage out of

11

Total no. of

cases

Percentage out of

30

Bronchial asthma

2 10.52 0 0 2 6.67

Diabetes mellitus

1 5.26 10 90 11 36.67

Renal Failure

0 0 1 9.09 1 3.33

Non-invasive fungal sinusitis Invasive fungal sinusitis

2

0

1

10

0

1

Chart No.6: Associated DiseasesBronchial asthma Diabetes mellitus Renal Failure

83

TABLE NO. 7: CT FINDINGS

CT Findings No. of cases with non-

invasive fungal

sinusitis

Percentage out of 19

No. of cases with

invasive fungal

sinusitis

Percentage out of 11

Total no. of cases

Percentage out of 30

Heterogenous opacity in sinonasal

compartments

6 31.57 2 18.18 8 26.66

Radiodensity in sinonasal

compartments

3 15.78 1 9.09 4 13.33

Bony invasion & destruction

0 0 10 90.90 10 33.33

Polypoidal mass

13 68.42 0 0 13 43.33

Mucosal thickening

9 47.36 9 81.81 18 60

Hetergenous enhancing

lesion

0 0 9 81.81 9 30

Proptosis 1 5.26 6 54.54 7 23.33Orbital

invasion0 0 6 54.54 6 20

Intracranial extension

0 0 2 18.18 2 6.66

Heterogenous opacity in sinonasal compartments

Radiodensity in sinonasal compartments

Bony invasion & destruction

Polypoidal mass

Mucosal thickening

Hetergenous enhancing lesion

Proptosis

Orbital invasion

Intracranial extension

0 2 4 6 8 10 12 14 16 18

6

3

0

13

9

0

1

0

0

2

1

10

0

9

9

6

6

2

Non-invasive fungal sinusitis Invasive fungal sinusitis

84

ChartNo. 7: CT findings

TABLE NO. 8: ENDOSCOPIC FINDINGS

Endoscopic findings

No. of cases with non-

invasive fungal

sinusitis

Percentage out of 19

No. of cases with

invasive fungal

sinusitis

Percentage out of 11

Total no. of cases

Percentage out of 30

Grey fungal debris

8 42.10 2 18.18 10 33.33

Polyposis 12 63.15 0 0 12 40Thick clay like

material in sinuses

2 10.52 0 0 2 6.66

Mucopus 3 15.78 1 9.09 4 13.33Fungal

colonisation on nasal crusts

1 5.26 0 0 1 3.33

Pallor of middle

turbinate

0 0 5 45.45 5 16.66

Black eschar 0 0 5 45.45 5 16.66Nasal crusts 2 10.52 4 36.36 6 20

Allergic mucin 11 57.89 0 0 11 36.66

Grey fungal debris

Polyposis

Thick clay like material in sinuses

Mucopus

Fungal colonisation on nasal crusts

Pallor of middle turbinate

Black eschar

Nasal crusts

Allergic mucin

8

12

2

3

1

0

0

2

11

2

0

0

1

0

5

5

4

0

Chart No. 8: Endoscopic Findingsinvasive fungal sinusitis non-invasive fungal sinusitis

85

TABLE NO. 9: MEDICAL TREATMENT

Medical treatment

No. of cases with non-

invasive

fungal sinusiti

s

Percentage out of

19

No. of cases with

invasive

fungal sinusiti

s

Percentage out of

11

Total no. of

cases

Percentage out of

30

Topical steroids

18 94.73 0 0 18 60

Systemic steroids

18 94.73 0 0 18 60

Oral Itraconazole

17 89.47 0 0 17 56.66

Topical Amphoteric

in B

0 0 9 81.81 9 30

Systemic Amphoteric

in B

0 0 11 100 11 36.66

Topica

l stero

ids

Syste

mic ster

oids

Oral Itr

aconazo

le

Topica

l Amphoter

icin B

Syste

mic Amphoter

icin B

18 1817

00

0 00

9 11

Chart No. 9: Medical Treatmentnon-invasive fungal sinusitis invasive fungal sinusitis

86

TABLE NO. 10: SURGICAL TREATMENT

Sugical treatment

No. of cases with non-

invasive

fungal sinusiti

s

Percentage out of

19

No. of cases with

invasive

fungal sinusiti

s

Percentage out of

11

Total no. of

cases

Percentage out of

30

FESS 18 94.73 0 0 18 60Endoscopic debridemen

t

0 0 8 72.72 8 26.66

DNE 1 5.26 0 0 1 3.33Endoscopic debridemen

t with maxillecto

my

0 0 1 9.09 1 3.33

Endoscopic debridemen

t with orbital

exentration

0 0 2 18.18 2 6.66

FESS

Endo

scop

ic de

brid

emen

t

DNE

Endo

scop

ic de

brid

emen

t w

ith m

axill

ecto

my

Endo

scop

ic de

brid

emen

t w

ith o

rbita

l exe

ntra

tion

18

0 1 0 0

0

80 1 2

Chart No. 10: Surgical treatmentnon-invasive fungal sinusitis invasive fungal sinusitis

87

TABLE NO. 11: CULTURE REPORTS

Culture Reports No. of cases with non-

invasive

fungal sinusit

is

Percentage out of

19

No. of cases with

invasive

fungal sinusit

is

Percentage out of

11

Total

no. of

cases

Percentage out of

30

Aspergillusfumigatus

1 5.26 2 18.18 3 10

Aspergillusflavus

3 15.78 2 18.18 5 16.66

Aspergillusniger 2 10.52 1 9.09 3 10Rhizopus 0 0 4 36.36 4 13.33

Others 1 5.26 1 9.09 2 6.67Negative 12 63.15 1 9.09 13 43.33

Aspergillus fumigatus

Aspergillus flavus

Aspergillus niger

Rhizopus

Others

Negative

1

3

2

0

1

12

2

2

1

4

1

1

Chart No. 11: Culture Reportsinvasive fungal sinusitis non-invasive fungal sinusitis

88

TABLE NO. 12: HISTOPATHOLOGICAL REPORTS

Histo-

Pathological

reports

No. of

cases

with

non-

invasive

fungal

sinusitis

Percentage

out of 19

No. of

cases with

invasive

fungal

sinusitis

Percentage

out of 11

Total

no. of

cases

Percentage

out of 30

Inflammatory

polyp without

fungal invasion

14 73.68 0 0 14 46.67

Aspergillosis 0 0 3 27.27 3 10

Mucormycosis 0 0 8 72.72 8 26.66

non-invasive fungal sinusitis

invasive fungal sinusitis

14

00

3

0

8

Chart No. 12: Histopathological reportsInflammatory polyp without fungal invasion AspergillosisMucormycosis

89

TABLE NO. 13: PROGNOSIS

Prognosis No. of

cases

with

non-

invasive

fungal

sinusitis

Percentag

e out of 19

No. of

cases

with

invasive

fungal

sinusitis

Percentag

e out of 11

Total

no.

of

cases

Percentag

e out of 30

Disease

free

17 89.47 7 63.63 24 80

Recurrence 2 10.52 0 0 2 6.67

Death 0 0 4 36.36 4 13.33

non-invasive fungal sinusitis

invasive fungal sinusitis

0

2

4

6

8

10

12

14

16

18 17

7

2

0

0

4

Chart No. 13: Prognosis

Disease free Recurrence Death

DISCUSSION

90

In this prospective study, the clinical profiles, investigations and

management of patients with fungal rhinosinusitis were studied from July

2009 to October 2011.

Diagnostic analysis:

In this present study which included 30 patients of fungal

rhinosinusitis 19 (63.33%) patients were diagnosed to have non-invasive

fungal rhinosinusitis of which 16 patients (53.33%) had allergic fungal

rhinosinusitis, 2 patients (6.67%) had fungal balls and 1 patient (3.33%)

had saprophytic fungal colonisation. The remaining 11 patients (36.67%)

had invasive fungal rhinosinusitis. Out of 11 patients, 9 (30%) were of

acute fulminant variety while 1 case (3.33%) was of chronic invasive type

and 1 (3.33%) was of chronic granulomatous type.

Age :

In our study of the 30 patients, majority of cases were between 41

to 50 years of age forming 26.67% of cases. The youngest patient was 15

years old and the oldest being 65 years. Of all the cases of non-invasive

fungal sinusitis, the cases with allergic fungal rhinosinusitis were from 15

to 65 years of age. The cases with fungal balls were from 33 to 35 years of

age and the cases with acute fulminant invasive fungal rhinosinusitis were

from 33 to 65 years of age and both the cases of chronic invasive fungal

rhinosinusitis were between 55 to 65 years. The mean ages of various

series of allergic fungal rhinosinusitis ranged from 23 to 42.4 years of

age.15,16 The average age reported for patients with fungal ball in an

American retrospective series of 29 cases was 64 years, ranging from 28

91

to 86 years.26 A comprehensive review by deShazo and Klossek also

showed a similar age range, with the youngest reported age being 18

years.25,27 Patients reported infected with rhino-cerebral mucormycosis

range in age from 16 days to 75 years according to Berrylin J. Ferguson.11

Sex:

In our study males were almost equally affected with fungal

rhinosinusitis compared to females. Of the 30 patients studied 16 were

males (53.33%) and 14 were females (46.66%). Of the 19 cases of non-

invasive fungal rhinosinusitis 11 patients were females and 8 patients were

males. Of the 11cases of invasive fungal rhinosinusitis 8 patients were

males and 3 patients were females. Of the 16 cases of allergic fungal

rhinosinusitis, 10 were females and 6 were males with a female

preponderance of 1.6 females per males. Some studies have noted a fairly

equal sex predilection for AFRS whereas Manning and Holman noted a

male predominance of 1.6males per female.16,17

Signs and symptoms:

In the present study nasal obstruction was the most common

presenting symptom noted in 29 patients i.e. 96.67% of cases. 15 out of

30 patients (50%) had nasal discharge. 21 out of the 30 (70%) patients

had headache. Nasal polyposis was the most common finding on local

examination in patients with non-invasive fungal rhinosinusitis. 12 out of 16

(75%)of the patients of our study with AFRS had polyposis.

92

The incidence of polyposis in AFRS reported in literature is almost

100%.17 According to Berrylin J. Ferguson the most common symptoms of

fungal ball are nasal obstruction, nasal discharge and facial pain. These

symptoms were present in both the patients having fungal ball in the

present series. The literature has reported that 10% of patients with fungal

ball have polyp27 which was present in both these patients in this series.

In our study comprising 11 patients of invasive fungal rhinosinusitis,

6 patients had fever (54.54%), 8 had facial swelling (72.72%) 4 had

deviation of angle of mouth (36.36%), 7 had diminution of vision (63.63%)

and paraesthesia (72.72%) was present in 8 patients. These symptoms

were absent in cases with non-invasive fungal rhinosinusitis. Proptosis

(63.63%), opthalmoplegia (63.63%), ptosis (63.63%) and palatal erosion

(27.27%) were also seen in invasive fungal rhinosinusitis.

According to Kennedy, Adams and Neglia the most common

symptom in acute fulminant invasive fungal rhinosinusitis is fever present

in upto 90% of patients. Facial pain, nasal discharge and headache are

variably present in 20% to 60% of such patients.29,30,32

Berrylin J. Ferguson has reported facial numbness as an early

symptom in 7% of cases.11 He believes that it is an under representation of

an early symptom that is not usually assessed.

According to Yohia and colleagues who reviewed 114 cases of

rhino-orbital-cerebral mucormycosis from the literature, nasal ulcerations

occurred in approximately one third of cases.46 Opthalmoplegia was

present in 29% of patients, proptosis in 16% of patients, nasal discharge in

93

18% of patients and palatal necrosis in 14% of patients. Harold et al found

decreased vision in 92% of patients and cranial nerve palsies in 77% of

patients of rhino- orbital-cerebralmucormycosis.52

In our study, out of 19 cases of non-invasive fungal rhinosinusitis, 2

patients (10.52%) had history of Bronchial Asthma. Studies have revealed

that one-third to one-half of the patients with allergic fungal rhinosinusitis

have asthma.17

In our series, 11 out of 30 patients (36.67%) had associated

Diabetes mellitus, in which 1 (5.26%) case was on non-invasive variety

and 10 (90%) were of invasive fungal rhinosinusitis. In the largest series

to date 126 patients with rhino-cerebral-mucormycosis, 70% of patients

were diabetic.11 Uncontrolled diabetes was the commonest underlying

disease in 30 (88.2%) of the 34 patients with histopathological diagnosis of

rhino-orbito-cerebral mucormycosis studied by Nithyanandam S et al.53

None of our patients in the present series had HIV or AIDS. The

literature has only 12 reported cases of mucormycosis for all organs in

AIDS patients.53

Radiological finding:

In our study, mucosal thickening was the most common finding

(60%) in CT-PNS of the patients with fungal rhinosinusitis.

Polypoid masses were seen in 13 of the 19 (68.42%) patients with

non-invasive fungal rhinosinusitis. Heterogenous opacity in sinonasal

compartments was seen in 6 (31.57%) patients of non-invasive fungal

94

rhinosinusitis while radiodensity in sinonasal compartments was seen in 3

(15.78%) patients with non-invasive fungal rhinosinusitis.

In the series by Klossek et al, on CT-PNS, 97 of 109 cases of

fungal balls showed heterogenous opacities and upto half of the cases

demonstrated radiodensities with central portion of the soft tissue mass.39

One of the 2(50%) patients of fungal ball in the present series had

antrochoanal polyp. Presence of antrochoanal polyp in fungal ball patients

has been reported by B. J.Ferguson.24 Both patients with fungal ball had

heterogenous opacities in sinonasal compartment in our series.

Heterogenous enhancing lesion (81.81%), bony invasion and

destruction (90.90%), orbital invasion (54.54%) and intracranial extension

(18.18%) were present exclusively in CT scans of patients with invasive

fungal rhinosinusitis in our study.

Andrew Blitzer et al had observed mucosal thickening in 60% of the

patients and bony erosion in 50% of patients with rhino-orbital-cerebral

mucormycosis.9

Endoscopic findings :

In our study, the most common endoscopic finding in cases with

non-invasive fungal rhinosinusitis was polyposis found in 12 patients

(63.15%) followed by gray fungal debris with clay like consistency found in

8 (42.10%) patients. Allergic mucin was present in 11 out of 16 (68.75%)

patients with allergic fungal rhinosinusitis Both patients of fungal ball had

thick clay-like material in sinuses. Fungal colonisation on nasal crusts was

95

found in 1 patient (5.26%) who was diagnosed to have saprophytic

colonisation.

The incidence of polyposis in AFRS reported in literature is almost

100%.17

In our series, pallor of middle turbinate (45.45%) and black eschar

(45.45%) were the most common findings in cases with invasive fungal

rhinosinusitis, followed by nasal crusts (36.36%), black necrotic debris with

coal-tar like consistency (18.18%) and mucopus(9.09%).

According to Christopher N. Prichard pallor of middle turbinate is

the earliest endoscopic finding in patients with invasive fungal

rhinosinusitis.10 Gillespie and O’ Malley have examined the role of middle

turbinate biopsy for the diagnosis of invasive fungal rhinosinusitis with 75%

sensitivity and 100% specificity.28

Surgical treatment:

Functional endoscopic sinus surgery (FESS) was the surgical

treatment in 18 out of 19 (94.43%) patients with non-invasive fungal

rhinosinusitis. Endoscopic removal of nasal crusts was done in 1 patient

with saprophytic colonization.

Mabry et al call FESS as a conservative but complete surgery

relying upon it completely.48

2 of the 19 (10.52%) patients with non-invasive fungal rhinosinusitis

had recurrence at 6 months follow-up of which one was treated by revision

surgery and the other was treated conservatively.

96

None of the two patients with fungal ball had recurrence after

surgery.

Waxman et al reported 3 groups of AFRS patients, those with

immediate recurrence within a matter of months after treatment, delayed

recurrence after a year or more and cured patients who were free of

symptoms with the follow up to 2 years.23

In our study, all the 8 patients with invasive fungal rhinosinusitis

were treated by endoscopic debridement. Orbital exenteration was done in

addition to endoscopic debridement in 2 patients- 1 (11.11%) with acute

invasive fungal rhinosinusitis and other with chronic granulomatous

disease. The patient with chronic invasive fungal rhinosinusitis required

additional maxillectomy for palatal involvement and antrocutaneous fistula.

After 6 months of disease free follow-up, the patient with chronic

invasive disease was treated with Left facial reconstruction and palatal

prosthesis and the orbital defect of the patient with chronic granulomatous

disease was reconstructed using free antero-lateral thigh flap. Both these

patients are still under follow-up.

In our present study 4 out of the 10 (40%) patients who underwent

endoscopic debridement with achievement of disease free bleeding

margins died. All of these 4 patients who died had orbital involvement and

one patient had intracranial involvement. In a series of Kennedy et al all 6

patients with orbital and intracranial involvement died of invasive fungal

disease.30

97

Orbital exenteration was once advocated for ocular involvement if

blindness had occurred. This is now controversial and there are several

case reports of patients surviving episodes of mucormycosis with ocular

involvement and blindness who did not undergo orbital exenteration.

These cases must be individualized according to Berrylin J. Ferguson.11

We feel that surgery should be tailor-made to suit the extent of the

disease in each patient.

Medical treatment:

In our study, topical steroids and systemic steroids were used in 18

out of 19 patients (94.73%) with non-invasive fungal rhinosinusitis. 1

(3.33%) patient with saprophytic colonization was not given steroids. Oral

Itraconazole was used in 17 (89.47 %) patients with non-invasive fungal

rhinosinusitis with a success rate of about 88.23%.

Agarwal et al recommend the use of oral Itraconazole in a dose of

400mg per day for 10 days.55 Rains et al reported retrospectively on 139

patients with AFRS treated with steroids and post-operative Itraconazole,

where they found that this regime may reduce the need for revision

surgery.56 Topical and systemic antifungal therapy for AFRS patients has

been studied by Kuhn et al with mixed to poor results.22 Waxman et al

suggested the use of systemic corticosteroids post-operatively.23 10 out of

26 patients studied by Kupferberg et al, who after surgery received

prednisolone therapy, reported lesser incidence of endoscopically

confirmed disease, on follow up.57 A 4-year follow up study of 11 AFRS

patients by Kuhn and Javer demonstrated a reduction in mucosal stage

98

and IgE level post operatively while the patients were on systemic

steroids.22

In our study, topical Amphotericin B douches were used in 7 out of

9 (77.77%) cases of acute invasive fungal rhinosinusitis with success rate

of 77.77% and in both cases (2) of chronic invasive fungal rhinosinusitis

with success rate of 100%. None of the patients with non-invasive fungal

sinusitis were treated with Amphotericin B douches.

As reported by A Helbling et al Amphotericin B nasal spray has no

effect on nasal polyp.58 Trigg et al have reported decrease in the incidence

of invasive fungal disease from 13.8% to 1.8% in neutropenic patients by

the use of Amphotericin B in the spray form.26Berrylin et al has

recommended topical application of Amphotericin B with 15mg vial of the

drug and 10ml sterile water.11

In our series, systemic Amphotericin B was used in all 9 patients

with acute invasive fungal rhinosinusitis, in a dose of 0.5mg/ kg/day over a

period of 6 weeks, with a success rate of about 55.55% as compared with

a 79% survival rate quoted by Andrew Blitzer et al.352 patients of chronic

invasive variety also received systemic Amphotericin B with a success rate

of 100%. Randal S. Weber et al reported excellent results with liposomal

Amphotericin B i.e. 71% in cases of invasive fungal infections.64 High dose

Amphotericin B is an important adjunct in the treatment of invasive fungal

rhinosinusitis. However Amphotericin B alone without surgery is thought

be insufficient in treatment of invasive fungal rhinosinusitis.

99

KOH mounts and culture reports:

In our study, intraoperative KOH mounts of all patients of fungal

sinusitis patients were positive.

Aspergillus flavus was the most common organism (16.66%) grown

on fungal culture of all patients with fungal rhinosinusitis. According to

case reports of paranasal sinus mycoses from India and Sudan,

Aspergillus flavus is the most common isolated organism on fungal

cultures.55

Rhizopus was the commonest organism (36.36%) grown on fungal

culture of all patients with acute invasive fungal rhinosinusitis in our study.

As reported by A Daudia et al the commonest causes of acute

fulminant fungal sinusitis are moulds of the mucorales order, including

rhizopus and rhizomucor species.59Aspergillusfumigatus is the most

frequently isolated species in both invasive arid non-invasive fungal

sinusitis in immunocompetent as well as immunocompromised patients.56

Other pathogens include those belonging to the family Mucoraceae

including the genera Mucor, Rhizopus and Absidia.

Negative cultures were found in 63.15% of patients with non-

invasive fungal rhinosinusitis and in 9.09% of patients with acute invasive

fungal rhinosinusitis.

100

Histopathological findings:

Inflammatory polyp without evidence of fungal invasion but with

eosinophilic infiltrate was the most common histopathological finding in 14

out of 19 (73.68%) cases with non-invasive fungal rhinosinusitis. 3 of the

14 (21.42%) patients with non-invasive fungal rhinosinusitis who had

inflammatory polyp on histopathological examination showed positive

fungal culture. Aspergillus flavus was isolated in two of these cultures and

Aspergillus niger in 1 culture.In a study of 100 polyposis patients by

Kordbacheh et al, 9 cultures yielded pure growth of fungi with Aspergillus

flavus as the most common organism.60

Absence of allergic mucin in histopathological examination of these

patients may be due to preoperative treatment with topical and systemic

steroids in our study. Pre-operative steroids cause resolution of

eosinophilic mucin and may obscure the diagnosis of AFRS according to

Graham and Ballas.61

In our study, of all the 11 patients of invasive fungal rhinosinusitis 5

patients (45.45%) had Aspergillosis on histopathological examination.

Prognosis:

Of all the 19 cases with non-invasive fungal rhinosinusitis 17

patients (89.47%) were disease free at 6 months follow up, whereas 2

patients (10.52%) had recurrence.

Of the 9 cases with acute invasive fungal rhinosinusitis 5 patients

(55.55%) were disease free at 6 months follow-up, while 4 patients

101

(44.44%) succumbed to death. All of these 4 patients had intraorbital

extension while one patient had intracranial extension of the disease.

Out of the 11 cases with invasive fungal rhinosinusitis 4 had only

sinonasal disease, all of which survived with a success rate of 100%.

Both the cases of chronic invasive variety were disease free after 6

months follow-up with 100% success rate.

In a series by Nithyanandam S et al, a success rate of 91% was

found in patients with sinonasal invasive fungal disease.53 Andrew Biitzer

et al reported 78% survival in cases with paranasal mucormycosis.35

Out of the 2 cases with intracranial extension 1 has survived and is

on regular follow-up. Thus we had a 50% survival rate in rhino-orbito-

cerebral mucormycosis cases. In our study we had about 63% survival

rate with medical and surgical line of treatment in mucormycosis

comparable with 84% survival rate reported by Harold Pillsbury et al.42

According to Gillespie and O’Malley a mortality rate of 100% has been

demonstrated in patients with intracranial involvement.26 In a series of

Kennedy et al, all 6 patients with orbital and intracranial involvement died

of invasive fungal disease.28

102

SUMMARY AND CONCLUSIONS

This was a prospective study comprising of 30 patients suffering

from Fungal Rhinosinusitis. Following conclusions were drawn from the

study.

1. Fungal Rhinosinusitis was found to be more common between

the age group 40 to 50 years (8 out of 30; 26.67%). Non-invasive fungal

rhinosinusitis was more common in younger age group between 20-

50years (13 out of 19; 68.42%) whereas invasive fungal rhinosinusitis was

more common in the older population between 40-70 years (10 out of 11;

90.90%).

2. There was a slight male preponderance as compared to females

in the overall incidence of fungal rhinosinusitis (16 males & 14 females;

53.33%). Non-invasive fungal rhinosinusitis was more common in females

(11 out of 19; 57.89%) whereas invasive fungal rhinosinusitis was more

common in males (8 out of 11; 72.72%).

3. The common clinical features of fungal rhinosinusitis were nasal

obstruction, nasal discharge, and headache and were present in both

invasive and non-invasive forms. Excessive sneezing was seen only in

cases with non-invasive fungal rhinosinusitis, whereas fever, facial

swelling, deviation of angle of mouth, diminution of vision and

paraesthesia was seen only in cases with invasive fungal rhinosinusitis.

Nasal polyposis was the most common finding on local examination in

patients with non-invasive fungal rhinosinusitis (12 out of 19; 63.15%),

103

whereas proptosis, opthalmoplegia, ptosis and palatal erosion were seen

in invasive fungal rhinosinusitis.

4. Invasive fungal infection was commonly seen in

immunosuppressed and immunocompromised patients such as patients

with diabetes mellitus (10 out 0f 11; 90%), renal failure (1 out of 11;

9.09%) etc. Bronchial asthma may be associated with non-invasive fungal

rhinosinusitis.

5. Computed Tomography and Magnetic Resonance Imaging are of

utmost importance to know the extension of the disease and also in the

management of the patients. Mucosal thickening was the most common

finding in CT-PNS of all the patients with fungal rhinosinusitis (18 out of

30; 60%). Polypoidal masses (13 out of 19; 68.42%), heterogenous

opacity and radiodensity in sinonasal compartments (6 out of 19; 31.57%)

were seen in patients with non-invasive fungal rhinosinusitis.

Heterogenous enhancing lesion, bony invasion and destruction, orbital

invasion and intracranial extension were present exclusively in CT scans

of patients with invasive fungal rhinosinusitis.

6. The most common endoscopic finding in cases with non-invasive

fungal rhinosinusitis were polyposis (12 out of 19; 63.15%), allergic mucin

(11 out of 19; 57.89%) and grey fungal debris (8 out of 19; 42.10%). Pallor

of middle turbinate (5 out of 11; 45.45%) and black eschar were the most

common findings in cases with invasive fungal rhinosinusitis.

7. Aspergillus flavus was the most common organism grown on

fungal culture of all patients with fungal rhinosinusitis (5 out of 30;

104

16.66%). Rhizopus was the commonest organism grown on fungal culture

of all patients with acute invasive fungal rhinosinusitis (4 out of 11;

36.36%).

8. Inflammatory polyp without fungal invasion but with eosinophilic

infiltrate was the most common histopathological finding in patients of non-

invasive fungal sinusitis (14 out of 19; 73.68%) while mucormycosis was

the most common histopathological finding in invasive fungal sinusitis (8

out of 11; 72.72%).

9. Treatment of choice was surgical debridement along with either

oral or systemic antifungals. Topical and systemic steroids were used only

in non-invasive fungal rhinosinusitis. Systemic Amphotericin B was used in

all cases of invasive fungal rhinosinusitis.

10. Cases with non-invasive fungal rhinosinusitis had good

prognosis as compared with those of invasive fungal rhinosinusitis with a

cure rate of 89.47% (17 out of 19) and 63.63% (7 out of 11) respectively.

Acute invasive cases has poorer success rate (5 out of 9; 55.55%) while

chronic invasive cases had 100% success rate. A combination of medical

and surgical line of treatment improved the prognosis significantly.

11. Currently novel regimes for the treatment of invasive and non-

invasive fungal rhinosinusitis include oral Voriconazole, combination of

liposomal Amphotericin B and either an Echinocandin or Itraconazole or

both.

105

Finally, prompt diagnosis, reversal of predisposing conditions and

aggressive surgical debridement remain cornerstones of therapy for this

deadly disease.

106

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KEY TO MASTERCHART

p: present

a: absent

FESS: Functional endoscopic sinus surgery

IP: inflammatory polyp without fungal invasion

AS: Aspergillosis

AFRS: Allergic fungalrhinosinusitis

Aifs: Acute invasive fungal sinusitis

Cifs: Chronic invasive fungal rhinosinusitis

Cgfs: Chronic Granulomatous fungal rhinosinusitis

U: used

OI: oral itraconazole

IAB: Injectable Amphotericin B

SC: Saprophytic colonisation

BSL: Blood sugar level

Arf: Acute renal failure

Crf: Chronic renal failure

BUN: Blood urea nitrogen

NA: Not Applicable

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