Prognosis for allergic fungal sinusitis

Prognosis for allergic fungal sinusitis STEPHENB. KUPFERBERG,MD, JOHN R BENTIHI,MD, and FREDERICKA. KUHN, MD, Augusta and Savannah, Georgia

Allergic fungal sinusitis is a recently described clinical entity that has gained increased affention as a cause of chronic sinusitis. The diagnosis can be established by demonstrating (1) type I hypersensitivity confirmed by history, skin tests, or serology; (2) nasal polyposis; (3) characteristic CT scan; (4) eosinophilic mucus without fungal invasion into sinus tissue; and (5) positive fungal stain of sinus contents removed intraoperatively or during office endoscopy. The exact pathogenesis of allergic fungal sinusitis remains controversial, and no treatment modality has proved to be consistently effective. Several reports during the last decade have suggested that allergic fungal sinusitis recurs more frequently than chronic bacterial sinusitis, but no studies have specifically addressed the prognosis of allergic fungal sinusitis. During the past two and a half years, we have treated 26 patients with allergic fungal sinusitis. The treatment always included functional endoscopic sinus surgery, topical nasal steroids, postoperative nasal saline irrigations, and endoscopic cleaning in the office. Adjuvant medical therapy included systemic steroids, oral ontifungals, a combination of systemic steroids and oral antifungals, or in some cases, no additional treatment. Outcome was graded subjectively as improved, unchanged, or worse. Mean follow-up was 14.5 months. Twenty-two of 26 patients were improved. In reviewing postoperative outcomes, we observed endoscopic recurrent disease that generally preceded patient symptoms. Consequently, we developed an endoscopic staging system to record postoperative clinical status. Use of this staging system allowed evaluation of various treatments and enabled classification of patient outcome. Nineteen of 24 patients examined with extensive follow-up had objective signs of recurrent disease. It appears that this is a chronic disease characterized by physical signs that appear before the return of subjective clinical symptoms. (Otolaryngol Head Neck Surg 1997;117:35-41.)

F o u r types of fungal sinusitis are recognized currently, each with specific presentation and therapy. Acute or fulminant invasive fungal sinusitis, mainly effecting immunocompromised hosts, is a rapidly progressive and life-threatening infection. Treatment consists of surgical debridement and intravenous antifungal therapy. Chronic or indolent invasive fungal sinusitis primarily affects immunocompetent persons because the fungus proliferates in the sinus cavity and penetrates the mucous membrane of the affected sinus. Treatment is debridement and antifungal therapy. Mycetoma, more properly called fungus ball, expands within the confines of an immunocompetent, nonatopic host sinus

From the Medical Collegeof Georgia. Presented at the Annual Meeting of the American Academy of Otolaryngology-Headand Neck Surgery,San Diego, Calif., Sept. 18-21, 1994. Reprint requests: Stephen B. Kupferberg, MD, Division of Otolaryngology,Medical College of Georgia, BP-4109,Augusta, GA 30912-4060. Copyright © 1997 by the AmericanAcademy of OtolaryngologyHead and Neck SurgeryFoundation,Inc. 0194-5998/97/$5.00 + 0 23/1/74549

and does not invade or penetrate the sinus mucosa. Patients have few, if any, symptoms, and the fungus ball is removed by debridement. The final and most recently recognized type is allergic fungal sinusitis (AFS). The fungi colonize the sinus of an atopic and immunocompetent patient and act as the allergen, eliciting an immune response.

HISTORY Millar et al. ~ first recognized similarities between the histologic material obtained from the maxillary sinuses of five patients and those of pathologically diagnosed specimens of allergic bronchopulmonary aspergillosis (ABPA). Katzenstein et at. 2 then retrospectively reviewed 119 histologic specimens obtained from patients who had undergone prior sinus surgery. They found seven cases with mucin that contained eosinophils, Charcot-Leyden crystals, and fungal hyphae histologically resembling ABPA. They named this entity allergic Aspergillus sinusitis. Since 1986 several reports have documented fungi other than Aspergillus causing similar findings, prompting a name change to AFS. 3-9

35

OtolaryngologyHead and Neck Surgery July 1997

36 KUPFERBERGet al.

Fig. 1. CT scan revealing fungal debris filling the right maxillary and right ethmoid sinuses. Note erosion of the lateral nasal wall and resultant septal deformity.

PRESENTATION

AFS is being recognized with greater frequency as clinical suspicion has led to increased culturing of nasal secretion for fungus. CT revealing serpiginous densities in the sinuses also alerts one to AFS. The diagnosis of AFS should be entertained when nasal endoscopy reveals thick, tenacious mucus with polyposis in the patient who has undergone multiple sinus procedures. A review by Bent and Kuhn 1° defined the criteria necessary to diagnose AFS (Table 1). Although helpful, a positive fungal culture is not necessary for definitive diagnosis. The rapid evolution of techniques for culturing fungus should enable physicians to obtain a positive culture and increase the percentage of patients found to have multiple fungi identified. R A D I O G R A P H I C FINDINGS

CT reveals opaque sinus cavities with areas of attenuated signal density, especially prominent on bone window views 11 (Fig. 1). The soft tissue densities range from 100 to 125 Hounsfield units and correlate with the surgically removed fungal debris. 12 Bone erosion may be present but is caused by pressure remodeling rather than fungal invasion and destruction. MRI demonstrates isointense or slightly hypodense regions on Tl-weighted images and marked hypodensity on T2-weighted images, which correlate to fungus,

surrounded by mucosal inflammation with increased density 11 (Fig. 2). PATHOLOGY

Endoscopic evaluation demonstrates extremely thick, tenacious mucus ranging in color from yellow to green to brown. Attempts at suctioning are often met with frustration, and curettage and irrigation are needed for adequate removal. These fungal concretions, mycoliths (Fig. 3), should be sent to pathology for fungal stain and to microbiology for fungal, aerobic, and anaerobic culture. Histologic examination characteristically contains allergic mucin containing sheets of eosinophils, necrotic eosinophils, and cellular debris within an amorphous stroma. High-power examination reveals CharcotLeyden crystals with a hexagonal cross section and a bipyramidal longitudinal section (Fig, 4). Fungal hyphae are seen on Gomori's methenamine silver and KOH preparations. The pathologist should be cognizant of the presumptive diagnosis of AFS to closely examine the specimen for mucosal or bony invasion. Tissue invasion precludes the diagnosis of AFS and favors chronic invasive fungal sinusitis. METHODS A N D MATERIAL

A review of the charts of all patients suspected of meeting the criteria for AFS at the Medical College of

OtolaryngologyHead and Neck Surgery Volume 117 Number I

KUPFERBERG et al. 37

Fig. 2, MRI showing area of hypodensity in the sphenoid sinus that correlated to fungal debris removed intraoperatively.

Georgia, Augusta, Georgia, and Dwight D. Eisenhower Medical Center, Fort Gordon, Georgia, between November 1991 and October 1993 was performed. Twenty-six patients met all five criteria and were included in this study. Attention was directed to preoperative symptoms, prior operations, surgical findings, histology, culture results, and follow-up. All patients were then either contacted by phone or questioned in person. Each subjectively graded their postoperative symptoms as falling into one of three categories: improved, no change, or worse. Twenty-four patients underwent postoperative examination, and their disease was objectively staged in relation to the signs o f recurrence. We used a staging system based on endoscopic findings, reflecting incremental increases in grossly visible disease, as delineated in Table 2. Mean follow-up for these patients was 14.5 months. RESULTS

Twenty-six patients, 15 female and l 1 male, ranging in age from 13 to 69 years, underwent functional endoscopic sinus surgery (FESS) with removal of polyps and fungal debris. Each received standard postoperative care including nasal saline irrigations and endoscopic cleaning. Because this was a retrospective study, patients were not officially randomized into treatment protocols. Postoperative therapy varied from no additional treatment to a combination of oral antifungals used in conjunction with systemic steroids. In our

Fig. 3, Fungal concretion ("mycolith") being removed from left maxillary sinus.

patient population 10 patients received systemic steroids alone, 9 no treatment, 2 systemic steroids and oral antifungats, and 3 oral antifungals only. All of the 26 patients were questioned about their subjective symptoms. Twenty-two noted improvement, four were without change, and none was worse. Correlation of treatment with symptoms is summarized in Table 3.

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38 KUPFERBERGet al.

Fig. 4. Charcot-Leyden crystal on hematoxylin and eosin stain.

Table 1. Criteria for diagnosis of AFS Type I hypersensitivity confirmed by history, skin testing, or serology Nasal polyposis Characteristic CT scan Histologic evidence of eosinophilic mucus without evidence of fungal invasion into sinus tissue Positive fungal stain or culture of the sinus contents removed intraoperatively or during office endoscopy

Table 3. P o s t o p e r a t i v e t r e a t m e n t versus subjective stage Treatment

Improved

Systemic steroids Systemic steroids and antifungals Antifungals None TOTAL

No change

Worse Total

9 2

1 0

0 0

10 2

1 10 22

2 1 4

0 0 0

3 11

Table 2. O b j e c t i v e e n d o s c o p i c s t a g i n g system Stage 0 I II Ill

Criteria No evidence of disease Edematous mucosa/allergic mucin Polypoid mucosa/allergic mucin Polyps and fungal debris

Twenty-four patients underwent critical endoscopic examination for allergic mucin, edematous mucosa, polypoid mucosa, polyps, and fungal debris. Table 4 compares objective findings with patient symptoms, and Table 5 relates objective findings with postoperative treatment. Fungal cultures were positive in 22 of the 26 patients, with 5 patients having multiple fungi. The remaining 4 patients with negative cultures had hyphae on KOH or Gomori's methenamine silver preparations. Table 6 depicts culture results. Curvularia was the most common etiologic agent, All patient data are summarized in Table 7.

Table 4. O b j e c t i v e versus s u b j e c t i v e s t a g e No

Stage

0 I II III TOTAL

Improved

change

Worse

Total

5 2 7 6

0 0 2 2 4

0 0 0 0 0

5 2 9 8

20

DISCUSSION

The proper diagnosis of AFS is paramount, and ideally each individual should meet the defined criteria. Correctly establishing the diagnosis enables the initiation of optimal treatment, which includes FESS. Costly and lengthy courses of antibiotics, aggressive antifungal therapy, and patient and physician aggravation can be avoided with a high index of diagnostic suspicion. The pathophysiology of AFS remains controversial. Most authorities postulate that a ubiquitous fungus con-

OtolaryngologyH e a d and N e c k Surgery V o l u m e 117 N u m b e r 1

KUPFERBERG et al. 3e

T a b l e 5. P o s t o p e r a t i v e objective stage

treatment

Table 6. F u n g a l s p e c i e s

versus

Fungal species

Treatment Systemic steroids Systemic steroids and antifungaLs Antifungals No treatment TOTAL

NO.

of patients

i

Stage 0

I

II

III

Total

4 0

2 0

2 2

2 0

10 2

0 1 5

0 0 2

2 3 9

1 5 8

3 9

Alternaria Aspergilfus Bipolaris Cladosporium Curvutaria Drechslera Exserohilurn Fusarium Hyalinase Penicfllium

3 7 3 I I0 ! I I I I

Table 7. S u m m a r y t a b l e o f p a t i e n t s Patient no.

Age (yr)

Steroids 1 2 3 4 5 6 7 8 9 10 Antifungats 11 12 13 Steroids and antifungals 14 15 No treatment 16 17 18 19 20 21 22 23 24 Insufficient follow-up 25 26

Fungi

Subjective Stage

Curvu'aria

45 35 39 18 15 38 51 14 3O 69

Curvufaria Curvufaria Curvularia Altemaria Aspergillus, Penicillium Aspergillus Aspergillus Penic/lfium

64 56 20

0 m

8 17 9, (~)* 8 14 t! i1 28 11 8, (6)*

Aspergillus niger, Aspergillus flavus Bipolaris Dreschlera

Ill it if

t2 24 6

42 23

Curvularia, Aspergillus, Cladosporium, Alternaria Curvularia, Hyalinase, Fusarium

ii II

16 38

13 18 45 53 28 15 22 38 16

Bipolaris Curvularia Curvularia Exserohilum Aspe,'gillus

ii il I1 lil Ill 0 ll! ill Ill

12 3 4 34 2 22 I8 6 29

20 15

Curvularia Bipolaris

-

-

II II Ill 0 ! 0 0

Follow-up (me)

4

Curvularia

NA NA

/, Improved; N, no change; W, worse; NA, not applicable. *Time in parentheses is after second operation and not included in mean follow-up.

tacts sinus mucosa and proliferates. In certain predisposed immunocompetent atopic individuals, this causes an immune reaction producing mucosal thickening and the formation of allergic mucin and polyps. A concurrent rise in the IgE level accompanies the fungal proliferation, reproducing the model of ABPA. 13,14 The same scenario in a nonatopic host might result in a mycetoma or no sinus disease. Even with the best surgical treatment, it is unlikely that all fungal hyphae and spores can be removed. Therefore adjunctive medical therapy should be used.

The most efficacious modality to follow response to medical therapy was by critical nasal endoscopy with the objective staging as outlined in Table 2. Using Fischer's exact one-tailed test to compare patients who received postoperative systemic steroids with those who received no steroids, we maintained a greater number of patients in the steroid group with no or minimal recurrent disease (stages 0 and I) (p = 0.04). Six (60%) of 10 patients treated with steroids were maintained in stages 0 and I versus 1 (7.1%) of 14 for all other treatment modalities. The 2 patients receiving steroids who

OtolaryngologyHead and Neck Surgery July 1997

40 KUPFERBERGet aL

were in stage III have already undergone further FESS, and several others are scheduled for further procedures. Of the patients receiving no additional therapy, 8 (89.9%) of 9 are in stages II or III, and the 1 patient in stage 0 has received no long-term endoscopic follow-up (Table 5). Our current treatment regimen calls for routine use of adjuvant postoperative systemic steroids. This has caused a decrease in the inflammatory response, including a decrease in edema and polyp formation similar to their effect on ABPA. ~3 Several other authors have advocated the use of systemic steroids for this patient population. 5,6,12,15 The steroids should be administered or increased at any endoscopic sign of recurrence. The signs of recurrence are (1) mucosal edema, (2) allergic mucin, (3) polypoid edema, (4) polyps, and (5) fungal debris. Specifically, we advocate oral prednisone, for a typical 70 kg male, in the following dosages: 40 mg x 4 days, then 30 mg x 4 days, followed by 20 m g a day until their 1-month visit. The dose is then adjusted based on the patient's endoscopic staging and maintained at the lowest dose able to maintain stage 0. We frequently saw mucosal disease appear as the steroids were weaned, reinforcing the relationship between steroid level and mucosal stage. In our experience dosages of less than 15 mg every other day have led to recurrence. Also, it appears unlikely that any type of medical therapy can reverse advanced (stage II or III) disease. Anecdotal experience with orally administered fluconazole, ketoconazole, and miconazole has not demonstrated significant effect on the recurrence of AFS. At the present state of our knowledge, the proper length of steroid treatment is unknown. Postoperative endoscopic follow-up is extremely important. A comparison between the subjectively improved patients did not correlate well with their endoscopic examination. Overall, 22 (84.6%) of 26 patients subjectively felt improvement. However, only 5 (20.8%) of 24 had no objective evidence of disease. Clearly, the objective staging system does not correlate with patient symptoms. This lack of correlation may be attributed to the detection of endoscopic pathology before it manifest as symptomatic disease. Consequently, the objective endoscopic return of disease should be the standard by which further treatment is based because subjective symptoms lag behind endoscopic findings. Patients should undergo nasal endoscopy every 4 to 6 weeks to look for return of disease. Serially obtained total and fungal specific IgE levels may help the clinician evaluate therapeutic success, but these values have not yet been shown to correlate with either subjective or

objective manifestations of AFS. Endoscopic staging appears to be the most useful indication for adjusting steroid dosage. This staging system gives the clinician a framework on which to base the postoperative mucosal response to adjunctive medical therapy and the need for further surgery. It can also be used to assess patients before surgery if a positive endoscopic culture or fungal stain is obtained in the office setting and if the patient meets the remaining four criteria for a diagnosis of AFS. Waxman et al. 16 established three populations of patients with respect to the progression of their disease. One group was disease free after one surgical procedure. The other groups had either rapid or delayed recurrence. The speed of recurrence may be related to the amount of fungi and fungai antigen remaining after FESS or to individual variations in type I immunity. We believe that longer follow-up reveals more extensive subjective complaints and objective disease and that the vast majority of patients have chronic disease. Given the success of immune modification with steroids, perhaps the best opportunity to improve prognosis will be through immunotherapy. CONCLUSIONS

1. The diagnosis of AFS must be suspected, or it may be missed. 2. All patients will need FESS with regular, frequent endoscopic follow-up. 3. Our data demonstrate that patients who received postoperative steroids had less endoscopically confirmed disease. However, we observed the return of disease as steroids were weaned, indicating that steroids are not curative. 4. Patients found to have no recurrence may not have been followed up for an adequate interval. 5. The staging system gives a framework for the clinician to observe response to medical therapy and the need for further surgery. 6. The short-term prognosis for AFS is good, but the patient and physician should understand that with current treatments, this appears to be a chronic disease. REFERENCES

1. Millar JW, JohnstonA, Lamb D. Allergic aspergillosis of the maxillary sinuses [Abstract].Thorax 1981;36:710. 2. KatzensteinAA, Sale SR, GreenbergerPA. AllergicAspergillus sinusitis: a newly recognizedform of sinusitis. J Allergy Clin Immunol 1983;72:89-93. 3. KillingsworthSM, WetmoreSJ. Curvularia/Drechslera sinusitis. Laryngoscope1990;100:932-7.

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V o l u m e 117 N u m b e r 1

4. Bartynski JM, McCaffrey TV, Frigas E. Allergic fungal sinusitis secondary to dermataceous fungi--curvularia lunata and alWrnaria.Otolaryngol Head Neck Surg 1990;103:32-9. 5. Ence BK, Gourley DS, Jorgensen NL, et al. Allergic fungal sinusitis. Am J Rhinol 1990;4:169-78. 6, Allphin AL, Strauss M, Abdul-Karim FW. Allergic fungal sinusitis: problems in diagnosis and treatment. Laryngoscope 1991;101:815-20. 7. Gourley DS, Whisman BA, Jorgensen NL, Martin ME, Reid MJ. Bipolaris sinusitis: clinical and immunologic characteristics. J Allergy Clin Immunol 1990;85:583-9l. 8. Brummond W, Kurup VP, Harris OJ, Duncavage JA, Arkins JA. Allergic sino-orbital mycosis. A clinical and immunologic study. JAMA 1986;256:3249-53. 9. Manning SC, Schaefer SD, Close LG, Vuitch E Culture-positive allergic fungal snusitis. Arch Otolaryngol Head Neck Surg 1991;117:174-8.

Oi

tolaryngology-Head and Neck Surgery p r o v i d e s

10. Bent JE Kuhn FA. The diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1994;111:580-8= 11. Zinreich SJ, Kennedy DW, Malat J, et al. Fungal sinusitis: diagnosis with CT and MR imaging. Radiology 1988;169:439-44. 12. Schweitz AS, Oourley DS. Allergic fungal sinusitis. Allergy Proc 1992;!3:3-6. 13. Oreenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 1984;74:645-53. 14. Manning SC, Mabry RL, Schaefer SD, Close LG. Evidence of IgE-mediated hypersensitivity in allergic fungal sinusitis. Laryngoscope 1993;t03:717-21. 15. Corey JR Romberger CE Shaw GY. Fungal diseases of the sinuses. Otolaryngol Head Neck Surg 1990;103:1012-5. 16. Waxman JE, Spector JG, Sale SR, Katzenstein AA. Allergic Aspergillussinusitis: concepts in diagnosis and treatment of a new clinical entity. Laryngoscope 1987;97:261-6.

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