Dr.Surya Prakash D R MS ENT

PG TutorDepartment of ENT-III

Christian Medical College,Vellore.

01-06-2009

Fungal sinusitis Classification:

1. Acute/Fulminant, Invasive (immunocompromised host)

2. Chronic/Indolent, Invasive3. Fungal Ball 4. Allergic Fungal Sinusitis (AFS)

Classification: (Stammberger 2008 AAO-HNS)Invasive:

Acute Fulminant Invasive Fungal Sinusitis (AFIFS) Chronic Invasive Fungal Sinusitis (CIFS) Granulomatous Invasive Fungal Sinusitis (GIFS

Non-invasive: Saprophytic Fungal Infestation (SFI) Sinus Fungus Ball (SFB) Eosinophil Mediated Forms

Allergic Fungal Sinusitis ( AFS ) Eosinophilic Fungal Rhino-sinusitis (EFRS)

Transitional.

Introduction

1976 Safirstein: The combination of nasal polyposis, crust

formation, and sinus cultures yielding Aspergillus was first noted ,who observed the clinical similarity that this constellation of findings shared with allergic bronchopulmonary Aspergillosis (ABPA).

1981 Miller Reports described histologic similarities between

sinus mucin from patients with allergic fungal sinusitis and pulmonary secretions from patients with ABPA.

1983 Katzenstein A distinct mucinous material containing

eosinophils, Charcot-Leyden crystals, and fungal hyphae was found in tissue resected from the sinuses of 7 patients.This histologic appearance is identical to mucoid impaction occurring in bronchi in allergic bronchopulmonary aspergillosis

Allergic fungal sinusitis (or allergic fungal rhinosinusitis; AFRS) is a term introduced by Robson in 1989 to describe a constellation of unusual findings in a unique group of patients suffering from chronic sinusitis. 

Although AFRS represents the most common type of fungal sinus infection, our understanding of this disease is still limited.

Eosinophilic mucin rhinosinusitis (EMRS)? EMRS = AFS in the absence of fungal hyphae.EMRS occurs because of dysregulation of

immunologic controls involving upper and lower airway eosinophilia, whereas AFS is a localized IgE-mediated reaction to the germinated fungus.

EMRS: Systemic disease, therefore not unilateral Higher association with asthma, ASA sensitivity Increased incidence of IgG1 deficiency Older patients: avg 50’s

AFS: Allergic response to fungi Unilateral or bilateral Fungal immunotherapy and antifungal agents Younger patients: avg 30’s

Frequency: It is estimated that approximately 5-10% of

patients affected by chronic rhinosinusitis actually carry a diagnosis of AFS

The (M/F) ratio of AFS equal.Organism

Fungi implicated in AFS are known as the dematiaceous (darkly pigmented) fungi.Aspergillus spp, BipolarisCurvularia Alternaria

Pathogenesis Initiation of the inflammatory cascade

leading to AFS is a multifactorial event, requiring the simultaneous occurrence of such things as

IgE-mediated sensitivity (atopy), specific T-cell HLA receptor expression, exposure to specific fungi, and aberration of local mucosal defense

mechanisms.

The Natural HistoryAFRS must be distinguished from

other forms of fungal rhinosinusitis.  It is helpful to consider fungal

rhinosinusitis along an immunologic spectrum with reference to the host, irrespective of the offending fungi. 

The immunocompromised patient may develop invasive fungal rhinosinusitis, which is often rapidly fatal. 

The immunocompetent host may also develop invasive rhinosinusitis, though the course is generally much more chronic. 

Mycetomas, or fungus balls, occur in immunologically competent hosts and are almost never invasive. 

Saprophytic fungal aggregates are often seen endoscopically growing on dried crusts of mucus in areas of mucociliary transport disruption; these crusts with their saprophytic fungal growths seem to have no clinical importance. 

At the opposite end of the spectrum from the immunocompromised is the immunologically “hypercompetent,” the atopic patient.  It is in this host that AFRS manifests.

AFRS is initiated when an atopic individual is exposed to inhaled fungi. 

It is estimated that an active man will inhale

approximately 5.7 x 10⁷ spores of various species within a 24 hour period. 

The fungi deposits within a sinus cavity, and an escalating immunologic reaction, Gell and Coombs types I (and possibly III), takes place to the non-invading organism. 

Mucosal edema, stasis of secretions, and an inflammatory exudate all combine to obstruct the sinus ostia. 

The process may then expand to involve adjacent sinuses and may produce sinus expansion and bony erosion. 

Secondary bacterial infection may also occur, simulating an acute exacerbation of underlying chronic sinus disease.

Symptoms of AFRSSino nasal.Ocular.Complications.Cranial nerve deficits.

Similar to other chronic rhinosinusitis patients.  Typically has a history of nasal polyposis, and may have

had prior sinonasal surgery.  may have documented atopic disease.  Proptosis is common in children with AFRS.  Seventy-five percent of patients who are ultimately

diagnosed as having AFRS describe expelling darkly-colored rubbery nasal casts.  This is composed of the tenacious allergic mucin in which the hyphal forms can be found.

Ocular Manifestations82 patients Orbital involvement without visual loss was

found in 14.6% of the patients and most commonly resulted in

Proptosis (seen in 6.1% of patients) Telecanthus (seen in 7.3%). Visual loss from AFS, encountered in 3.7%

of patients, was reversible with immediate surgical treatment of the underlying disease.

Marple BF, Gibbs SR, Newcomer MT, Mabry RL: Allergic fungal sinusitis-induced visual loss. Am J Rhinol 1999,

Diagnosis Bent and Kuhn Diagnostic critreria

Five major criteria are: Evidence of type I hypersensitivity (IgE

mediated) by history, skin tests or serology.

Nasal polyposis.Characteristic computed tomography

findings. Eosinophilic mucus.Positive fungal stain.

Six associated criteria are asthma. (8/15) unilateral predominance. (13/15) radiographic bone erosion. (12/15)

fungal culture. (11/15)Charcot-Leyden crystals. (6/15)serum eosinophilia. (6/15)

Marple utilizes the same diagnostic criteria, though he excludes 4) as a negative culture may be due to laboratory inexperience, and a positive culture may represent a saprophytic growth of fungi.  In actuality, the atopic patient who lacks polyps, a characteristic CT and/or positive fungal cultures, but has the characteristic histopathology of allergic mucin with hyphal elements is still diagnosed as having AFRS.

It is important to realize that the diagnosis of AFRS is not established, nor eliminated based upon the results of these cultures. The variable yield of fungal cultures renders AFRS in the presence of a negative fungal culture quite possible.

Conversely, a positive fungal culture fails to confirm the diagnosis of AFRS, as it may merely represent the presence of saprophytic fungal growth. It is for this reason that the histologic appearance of allergic mucin remains the most reliable indicator of AFRS

Ig E levelsTotal IgE values generally are elevated in

AFS(90%)Total IgE level traditionally has been used to

monitor the clinical activity of allergic bronchopulmonary fungal disease.

IgE levels have been proposed as a useful indicator of AFS clinical activity.

Imaging in AFRS AFRS CT scan findings are characteristic.  Central areas of hyperattenuation within the sinus

cavity on CT scan correspond to areas of hypointensity on T1-weighted MR images, and signal void on T2-weighted MR images. 

These central ares represent the proteinaceous allergic mucin. The central high attenuation seen on CT scan may take on various patterns including a star-filled sky, ground glass, or serpiginous pattern.

Signal heterogentiy is due to accumulation of heavy metals (eg, iron and manganese) and calcium within inspissated allergic fungal mucin.

  Expansion, remodeling, or thinning of involved

sinus wall was common (98%) and was due to the expansile nature of the accumulating mucin.

Bony loss is common as the expanding inflammatory lesion pushes and thins surrounding bone.  The disease may progress from the frontal sinus into the orbit below, or posteriorly through the posterior table to involve the anterior skull base.  Disease may spread laterally from the ethmoid region to erode the lamina papyracea.  Although exposed, the soft tissue barriers of dura and periorbita are not invaded by the fungus.  Almost half of AFRS patients have only unilateral disease, although involvement of the nose and contiguous sinuses is common.

Allergic (Eosinophillic) mucinThe hallmark of AFSRemains the most reliable

indicator of AFSGrossly, allergic fungal

mucin is thick, tenacious, and highly viscous.

Peanut butter .

Allergic fungal mucin is normally first encountered at the time of surgery; therefore, recognition of its presence is the initial step in establishing an accurate diagnosis of AFS.

It is important to realize that it is the mucin, rather than paranasal sinus mucosa, that will provide the histological information necessary to make the diagnosis AFS.

Examination of mucosa and polyps obtained from involved paranasal sinuses reveal findings consistent with the inflammation of a chronic inflammatory process and should be done to establish that no fungal invasion is present.

Once mucin is collected, both culture and pathological examination is undertaken.

Delay in processing of the specimen more than six to eight hours after excision leads to degradation of fungal elements. Obtaining a positive KOH smear and/or fungal culture is of particular importance in cases of AFS in which histopathological examination is negative for fungal hyphae. One of the important factors in being able to demonstrate fungal hyphae in allergic mucin in patients with suspected allergic fungal sinusitis, is separation of specimens into polyps and allergic mucin. Detailed search of the former for evidence of absence of tissue invasion and of the latter for fungal hyphae lying loosely in the layered mucus, facilitates a conclusive diagnosis of allergic fungal sinusitis.

Histology Examination of the allergic mucin with a

hematoxylin and eosin stain reveals eosinophils, Charcot-Leyden crystals and, possibly, fungal hyphae within a background of eosinophilic or basophilic mucinous material. 

The Charcot-Leyden crystals are composed of lysophospholipase, and range in size from 2 to 60 micrometers. 

The crystals are depicted especially well with a Brown-Brenn stain. 

Gomori methenamine-silver stain is typically utilized to visualize the fungal elements within the allergic mucin. 

Fontana-Masson stain may actually allow the microscopist to more easily distinguish  the dematiaceous fungi from other septate fungi, as it stains the melanin which are characteristic of the former group and also provides a more clear background.

Fungal elements are recognized for their unique ability to absorb silver. This property is the basis for various silver stains, such as Grocott's or Gomori's Metamine silver (GMS) stain, which turn fungi black or dark brown .The use of a fungal stain complements the findings of initial H&E stain and is extremely important in the identification of fungi.

TREATMENTA variety of treatment plans for AFS have

emerged, but the potential for recidivism remains well recognized, ranging from 10% to nearly 100%, suggesting the need for continued study of this disease and fueling present controversy.

A comprehensive management plan incorporating both medical and surgical care remains the most likely way to provide long term disease control for AFRS.

Surgery The goals of surgical intervention are to eradicate

all allergic mucin, while simultaneously providing permanent drainage and ventilation for the affected sinuses.

Despite the controversy over the actual initiating factor, it appears that AFRS is an inflammatory response to fungi that leads to the production of mucin. The accumulation of mucin appears to play a role in the cyclic recurrence of the disease by way of perpetuating antigenic exposure .

In theory, complete surgical removal of mucin breaks this cycle.

Immunotherapy Immunotherapy administered in the presence

of an ongoing antigenic load (in this case fungus) raises the risk of untoward complications of therapy (immune complex deposition, delayed or late phase reactions, local reactions, etc.).

Antifungals Antifungal:

The benefit of systemic antifungal agents is unclear in the literature.

Amphotericin B, ketoconazole, itraconazole, and fluconazole have all been evaluated.

Mixed results have been reported; the drugs are expensive and sometimes dangerous

Regular evaluation of their LFT.

SteroidsPathophysiology:

Inhale sporesAntigen recognition +reactLymphocyte T-cells secreteIL-5 and IL-13Activate eosinophilsTravel through tissue towards sinus cavity and

mucusEosinophils attack germinating spores of hyphae

(not the hyphae themselves)Eosinophils release major basic protein (MBP)Toxic to epithelium (3000x)Epithelial damageEntry port for bacteria causing recurent-ABRS

Steroids: Reduce cytokines Inhibit production, migration and activation of

eosinophils. Lead to eosinophil apoptosis

Not address the underlying cause

Postoperatively, oral corticosteroid therapy is essential, but the dose of prednisone and the duration of treatment are debated.

oral prednisone in a dose of 40 mg (0.4 mg/kg) per day for 4 days, then to decrease the dose by 0.1 mg/kg/d in cycles of 4 days until a dose of 20 mg/d was reached (or 0.2 mg/kg/d, whichever is greater) .

At the 1-month postoperative visit, it is adjusted to 0.2 mg/kg/d. Monthly serum IgE levels were obtained.

The mucosa was maintained at stage 0 for 4 consecutive months on 0.2 mg/kg/d of prednisone;

The prednisone is reduced to 0.1 mg/kg/d for 2 months and intranasal steroid sprays were started at triple or quadruple the allergic rhinitis dose.

After 6 months of mucosal stage 0, the prednisone is discontinued and the intranasal steroids are continued as maintenance therapy.

Patients are currently seen on postoperative day 7, day 14, and day 42 and are then followed monthly with endoscopic examinations and total serum IgE levels until stable off of prednisone for at least 1 year.

They are followed every 2 months, since AFS can recur without symptoms at any time years later.

Patients treated with at least 2 months of oral corticosteroids were compared with those who received no corticosteroids. At 1 year after initial surgery, patients treated with oral corticosteroids were significantly less likely to have experienced recurrent AFS (35%) than those who had not (55%).

Allergic fungal sinusitis: diagnosis and treatment Frederick A. Kuhn, MD, FACS, and Ron Swain Jr., MD Current Opinion in Otolaryngology & Head and Neck Surgery 2003, 11:1–5

Kupferberg et. Al. refined the endoscopic follow-up into a proposed staging system, which allows closer control of the mucosal response to an oral steroid dose.

 •Stage 0 - No mucosal edema or allergic mucin•Stage 1 - Mucosal edema w/ without allergic

mucin•Stage 2 - Polypoid edema w/ without allergic

mucin•Stage 3 - Sinus polyps with fungal debris / mucin

Endoscopic mucosal staging

Stage 0 Stage I

Endoscopic mucosal staging

Stage II Stage III

The prognosis and optimum treatment of allergic fungal sinusitis are not yet clear.

Waxman reported three groups of patients: •Immediate recurrence•Delayed recurrence•Cure He reserved oral steroids for those patients who

recurred following surgery. The rationale for using oral steroids derives from the treatment of ABPA and the similarities between the two diseases.

All 10 of their surgery and Prednisone patients were treated with a Prednisone burst, then tapered to lower doses. He found that if the steroid dose was too low the mucosal stage increased, i.e., the disease became worse. This suggested that the mucosal stage and length of treatment are dose dependent and tied to some unknown factor, which responds to systemic steroids. He concluded that mucosal stage was a reflection of disease activity.

Thank You