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Allergic Aspergillus sinusitis: a newly recognized form of sinusitis
Allergic Aspergr’llus sinusitis: recognized form of sinusitis Anna-Luise A. Katzenstein, Paul A. Greenberger, M.D.
M.D., Scott St. Louis,
The clinical and pathologic features sinusitis are described. Most patients
MO.,
a newly
R. Sale, M.D., and and
Chicago,
Ill.
of seven cases of a newly recognized form of chronic were young adults with a history of asthma, and all had
chronic nasal polyps. Radiographically, there was opacijcation of multiple sinuses. Recurrent sinusitis was common, and several patients underwent numerous surgical drainage procedures. Histologically, a distinct mutinous material containing eosinophils, Charcot-Leyden crystals, and fungal hyphae was found in tissue resected from the sinuses. We believe that these jindings constitute a distinct clinicopathologic entity that we term allergic Aspergillus sinusitis. This condition shares similar histopathologic features with allergic bronchopulmonary aspergillosis (ABPA) but affects the paranasal sinuses rather than the lung. Implications for therapy of this form of sinusitis and its possible relationship to allergic lung diseases are discussed. (.I ALLERGY
CLIN IMMUNOL 7289-93,
1983.)
Mucoid impaction of the bronchi is one pathologic manifestation of ABPA. ‘3 * We recently encountered histologic findings indistinguishablefrom mucoid impaction of bronchi in tissue resected from the paranasalsinus of a patient undergoing surgery for chronic sinusitis. Fungal hyphae consistent with Aspergillus were also present within the impacted mutin. Similar changes have not been previously described in the paranasalsinuses,and they stimulated us to retrospectively review all tissue specimensremoved from the paranasalsinusesover a 5-year period. We identified six additional casesand compared them clinically and pathologically with examples of Aspergilfus mycetomas and nonallergic inflammatory conditions of the sinuses.We present evidence that the clinical and pathologic findings in these seven casescomprise a distinct entity possibly analogousto ABPA but occurring in the paranasalsinuses,and we
From the Department of Pathology, Washington University School of Medicine, St. Louis, MO. (A. L. A. K.), Department of Medicine, JewishHospitaIofSt. Louis, St. Louis, MO. (S. R. S.), and Northwestern University School of Medicine, Chicago, 111. (P. A. G.). Received for publication Oct. 25, 1982. Accepted for publication Jan. 27, 1983. Supported in part by the Ernest S. Bazley Grant and U.S.P.H.S. grant I 1403. Reprint requests: A. Katzenstein, M.D., Division of Surgical Pathology, University of Alabama Hospitals, 619 So. 19th St., Birmingham, AL 35233.
propose the name allergic Aspergillus sinusitis. The therapeutic implications of this condition and its possible relationship to allergic lung diseasesare discussed. MATERIALS
AND METHODS
Microscopicslideswerereviewedfrom 119 specimens surgically excised from the paranasal sinuses. These specimens included 113 consecutive cases in the Barnes Hospital SurgicalPathologyfilesfrom 1977to 1981that werecoded as acute and chronic inflammation, polyps, or mucoceles. An additional four cases coded as fungal infection between 1973 a?d 1977 were reviewed. One case was obtained from current surgical specimens at Jewish Hospital of St. Louis, and one was sent to Barnes Hospital for consultation. All slides were stained with H&E. The Gomori methenamine silver stain for fungi was used in all cases containing allergic or nonallergic mucin (see below) and in the six examples of mycetomas. The medical records were reviewed in pertinent cases, and when possible, individual patients were interviewed. Immediate cutaneous reactivity was determined in five individuals with Af and other common mold and inhalant allergens (Center Laboratories, Port Washington, N. Y .). Sera from the same patients were analyzed for precipitins to Af, total serum IgE, and IgG and IgE antibodies to Af.2, :$
RESULTS Pathologic findings Material that was indistinguishable from mucoid impaction of bronchi was found in the excised contents of the paranasalsinusesfrom nine patients. We 89
ABPA:
Allergic
H&E:
bronchopulmonary
aspergillosis
Hematoxylin-eosin stain
have termed this material ullergic mucin. It is characterized histologically by clumps of necrotic eosinophils and other cellular debris within a background of pale, eosinophilic-to-basophilic, amorphous mucin (Fig. 1). The necrotic cellular debris is frequently arranged in multilayered rows. Charcot-Leyden crystals. which appear hexagonal in cross section and bipyramidal in longitudinal section, were a consistent finding within the allergic mucin (Fig. 2, A). In seven cases thin, septate fungal hyphae that resembled Aspergillus species were found (Fig. 2, B ). The organisms occurred exclusively within the mucin, where they were scattered singly or in small clusters. There was no evidence of tissue invasion. We considered these seven patients to represent examples of allergic Aspergillus sinusitis. Eleven cases were identified in which there were varying amounts of a mutinous material that lacked the characteristic eosinophils and Charcot-Leyden crystals of allergic mucin. Sometimes neutrophils were prominent within this material, which we have termed nonullergic in$lammatory mucin. No fungi were found within this mucin. There were six examples of mycetomas of the paranasal sinuses. These lesions were characterized by densely packed, tangled masses of fungal hyphae that lacked associated allergic or nonallergic mucin. Morphologically the fungi were thin and septate and resembled Aspergillus species. There was no evidence of tissue invasion. The slides from the remaining 93 cases showed mainly nonspecific acute and chronic inflammation of sinus mucosa, inflammatory polyps, and mucoceles. They are not further discussed. Clinical
findings
Patients with allergic Aspergillus sinusitis. The clinical and radiographic features of the seven patients with allergic Aspergillus sinusitis are summarized in Table I. The mean age of these patients was 28 yr (range 13 to 48), with five between ages 13 and 25. Six patients had asthma (three in the past and three currently), and chronic nasal polyps were present in all. Three individuals were atopic. Radiographically, opacification of several or all paranasal sinuses was present. Bony erosion of the
sphenoid sinus was suspected in patient I. Chest rad!ographs were normal in all six individuals L-xamineii Three patients had a history of multlplc hrtr-gic~i procedures involving the paranasal sinuse:. Patient 2 had had five procedures in 6 years, inciudlnp hilatera? nasal antrostomies, bilateral Caldwell-Luc pr’ocedur~ (twice). a transeptal sphenoidectomy. ,md a frontai osteoplasty. Review of the tissue f‘rom these proic durea revealed allergic mucin containmg fun@ hyphae on three occasions. Patient 3 had had IO su-&al procedures on the nasal cavity and paranabal sinuses in 11 years. including five polypectomics. four Caldwell-Luc procedures. and remo! al (I!‘ a maxillary sinus cyst. Allergic mucin was found on three occasions. although hyphae were Identified in the mucin only once. Patient I had a nasal polypcctomy followed by a Caldwell-Luc procedure and ethmoidectomy 2 years later. On both occasions ailergic mucin containing hyphae was found. Patients rl,ith allergic mrrt,in \zYthout ~ir~lg!. ‘The sinus contents from two patients consisted of allergic mucin in which fungal hyphae could not be identified. These patients were 24 and 48 years old. Both had a history of asthma, chronic nasal polyps, and aspirin hypersensitivity. Opacification of several or all sinuses was seen radiographically. and chest radiographs were normal. Patients with nonallergic irzjkmmator~~ muc,in. The I I patients with nonallergic mucin formed a more heterogeneous group than the patients with allergic Aspergilllrs sinusitis. Their average age was 43 yr (range 17 to 721, and only one had a history ot asthma. In contrast to the patients with allergic .4spergillus sinusitis, more than one sinus was involved in only five individuals, one of whom had cystic fibrosis and one had diabetes with a history of prior invasive rhinocerebral mucormycosis. Bilateral sinusitis was present in the one patient with a history of asthma. Patients
with
myc’etomas
cf the paranusal
sinrcsrs~
The mean age of the six patients with mycetomas w’as 55 yr (range 29 to 65). None had a history of asthma. and a single sinus was involved in all cases (maxillary in five, sphenoid in one). Cutaneous in patients
reactivity and serobgic with aliergic &pu~~#&~
findings sinusitis
One of five patients with allergic Aspergillris sinusitis (patient 4) demonstrated immediate cutaneous activity to Af. Skin test results with several other common molds and inhalant allergens were positive in three individuals (patients 4, 5, 6). Sera were available from five patients with allergic
VOLUME NUMBER
72 1
Allergic
Aspergillus
sinusitis
91
FIG. 2. Higher-magnification photomicrographs of allergic mucin. A, Charcot-Leyden crystals that appear hexagonal in cross-section and bipyramidal in longitudinal section. (H&E; x350.) B, Thin, septate fungal hypha from a case of allergic Aspergillus sinusitis. (H&E; x480.)
FIG. 1. Low-magnification photomicrograph of allergic mucin showing clusters of darkly staining, focally necrotic eosinophils within a background of pale-staining amorphous mucin. Numerous Charcot-Leyden crystals can also be seen (arrows). (H&E; x90.)
Aspergillus sinusitis. They were obtained within several weeks of sinus surgery from patients 5,6, and 7, and in patients 3 and 4 they were obtained 4 and 1 yr after surgery, respectively. Total serum IgE levels were elevated in three individuals (patients 4, 6, 7) and precipitins to Af were detected in four (patients 4, 5, 6, 7). Serum from patients 4 and 6 demonstrated elevated IgG and IgE antibodies to Af, respectively, when compared with sera from asthmatics with cutaneous reactivity to Af but no other evidence for ABPA .3 DISCUSSION We describe seven patients with pathologic findings in the paranasal sinuses that are indistinguishable from mucoid impaction’ occurring in bronchi due to ABPA. The main feature of this lesion in both the sinuses and the bronchi is the presence of thick, inspissated mucoid material containing scattered fungal hyphae. This mucoid material, which we term allergic muck, has a distinct histologic appearance characterized by aggregates of necrotic eosinophils, nuclear
debris, free eosinophil granules, sloughed respiratory tract epithelial cells, and Charcot-Leyden crystals within an otherwise amorphous, pale eosinophilic or basophilic mutinous background. Clinically the patients with these findings comprised a relatively distinct and homogeneous group. Most were young adults with a history of asthma and nasal polyps. Radiographically, opacification of multiple paranasal sinuses was found. Three patients had recurrent sinusitis over several years and underwent numerous surgical procedures. We believe that these pathologic and clinical features constitute a previously unrecognized entity, and we have chosen the term “allergic Aspergillus sinusitis ” because of its histopathologic resemblance to ABPA .* Chest radiographs were normal in all six individuals with allergic Aspergillus sinusitis examined, and no one had a history of previous pneumonias or chest infiltrates that would suggest the possibility of ABPA. Serum precipitin reactions to Af were demonstrated in all but one patient tested, but elevated levels of both IgE and IgG antibodies to Af, which occur in ABPA, were not present .3 These serologic findings are similar to those described in patients with aspergillomas.4 We did not have serum available for comparison from patients with nonallergic mucin or mycetomas. Such studies, however, might prove helpful in the future to distinguish the groups of patients clinically. Safirstein” reported a patient with ABPA and nasal polyps who initially presented with rhinorrhea and the
92
Katzenstein
TABLE Case No. I
I. Clinical
et al.
features
of the
Age/Sex
Asthma
Atopy
I3/%1
No
No
patients
with
% Eos (total WC) NA
allergic Nasal polyps +
2
23/F
+
No
NA
+-
3
47/F
+
NO
3%(7
4
18/M
+
+
24%(5400)
+
5
27/F
+
+
3%(6100)
+
6
48/M
+
+
7%
+
7
17/F
+
No
NA
+
I oo)*
+
Aspet-gillus Sinus Opacification sphenoid: Opacitication ethmoid. Opacitication sinuses
sinusitis
films R maxillary, ?bony erosion R maxillary, frontal all paranasal
Opacification L maxillary antrum; mucosal thickening L ethmoid. sphenoid Opacification L frontal, maxillary; mucosal thickening L ethmoid Pansinusitis Opacification ethmoid,
L maxillary, sphenoid
-_ -_-__ ..---_ Surgical
procedure
R CMiwell-Luc.
ethrnoi&
cctomy , polypectomj Bilateral Caldwell-Lrri, polypectom} Bilateral Caldweil-Ltii, external ethmnidectomy L Caldwell-Luc.
Inferior turbinectomy; antrostomy
poiypectom)
L nasal
Bilateral Caldwetl-Luc. polypectomy L Caldwell-Luc, polypectomy
NA = not available; R = right; L = left. *Taking 10 mg of prednisone four times daily.
production of nasal casts. She was found radiographically to have opacified nasal sinuses.A Caldwell-Luc procedure and polypectomy were done and cultures of the excised material grew Af. Her nasal symptoms failed to improve and a lung infiltrate was noted several months after surgery. Although shehad no history of asthma, ABPA was diagnosedbecause of positive skin tests, serum precipitins to Af, and a pulmonary infiltrate with eosinophilia. Dramatic responseof the lung and nasallesionswasobtained with corticosteroid therapy. This patient likely had allergic Aspergiflus sinusitis similar to that of the patients described in this report, although the characteristic pathologic findings of this condition were not described. True infections due to Aspergillus species can occur in the paranasalsinuses,although they are not common.6-‘2 Invasive and noninvasive forms of infection have been described, and both differ clinically and pathologically from allergic Aspergilfus sinusitis. Invasive aspergillosisis characterized pathologically by tissue necrosisand a granulomatousreaction with fibrosis surrounding the organisms.*’ The infection may be relatively asymptomatic and slowly progressive ‘* R, lo or it may be a fulminant, life-threatening diseise, especially in immunocompromisedpersons.g Usually a single sinus is involved, and there is no particular association with asthma. A noninvasive form of Aspergillus infection may also occur, which is analogous to pulmonary mycetomas.12 The six mycetomasof paranasalsinusesreviewed in our study
were clearly different from casesof allergic Aspergillus sinusitis. Pathologically, they were characterized by large numbers of closely packed organismswithout accompanying allergic mucin. Clinically, the patients were older adults without evidence of asthmaor atopy, and only a single sinus was involved. It could be arguedthat the finding of fungal hyphae within allergic mucin in the paranasalsinusesreflects simply colonization of mucus by a ubiquitous fungus_ Several observations militate against this possibility. First, the histologic appearanceof allergic mucin containing fungi is identical to that of the lung lesion (mucoid impaction of bronchi), which is a welldocumentedmanifestation of ABPA. ‘CcSecond, if the fungus representednonspecific colonization, it should be present in examples of nonallergic as well as allergic mucin. We examined 11 casesof nonallergic mucin and none contained fungal hyphae. Third, although the casesof allergic Aspergillus sinusitiswere identified purely by histologic techniques, they manifested a distinct spectrumof clinical features, Similar associated, characteristic clinical features were not found in casesof nonallergic mucin or mycetomas 01 the paranasalsinuses. The role of fungal cultures in the further study of allergic Aspergillus sinusitis is questionable. The microbiology of chronic sinusitis has been extensively studied and has been found to include mainly aerobic and anaerobic bacteria with little reference to fungi. 14-16Since morphologically many of the fungi in allergic Aspergillus sinusitis appear to be degen-
VOLUME NUMBER
72 1
erating, it would not be surprising that they might be difficult to culture. The significance of the two cases of allergic mucin that did not contain fungi in our study is not clear. They may represent allergic Aspergilhs sinusitis in which, because of sampling difficulties, organisms were not identified. A similar phenomenon occurred in patient 3 who had multiple surgical procedures involving her sinuses. On one occasion, allergic mucin containing fungi was found, whereas at two other times allergic mucin lacking fungi was present. Another possible explanation for allergic mucin without fungi is that an allergen other than Aspergilfus, which may not be recognizable histologically, is responsible for the changes. Certainly, there are examples of mucoid impaction of bronchi that are of unknown etiology and cannot be attributed to ABPA.17 The optimal therapy for allergic Aspergitfw sinusitis needs to be prospectively investigated. Multiple recurrences were common in our cases after surgical drainage procedures. Dramatic improvement in both lung and nasal symptoms was obtained with corticosteroid therapy in the patient reported by Safirstein,5 and similar therapy may be useful in patients with allergic Aspergillus sinusitis. A possible relationship between allergic Aspergillus sinusitis and allergic diseases of the lung is purely speculative at this time. The association of chronic sinusitis and asthma has been known for many years, however, and improvement in asthma has been documented by some investigators after treatment of sinusitis.‘“, I6 Whether fungal antigens from the paranasal sinuses could aggravate asthmatic symptoms or whether they might have a role in the development of ABPA are unanswered questions. REFERENCES I. Katzenstein A, Liebow A, Friedman P: Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 111:197, 1975.
Allergic
Aspergillus
sinusitis
93
2. Rosenberg M, Patterson R, Mintzer R, et al: Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 86~405, 1977. 3. Wang JLF, Patterson R, Rosenberg M, Roberts M, Cooper BJ: Serum IgE and IgG antibody activity against Aspergillus fumigarus as a diagnostic aid in Allergic Bronchopulmonary Aspergillosis. Am Rev Respir Dis 117:917, 1978. 4. Patterson R, Wang JLF, Roberts M, Zeiss CR: Comparison of radioimmunoassay techniques in the detection of IgE and IgG antibody activity against Aspergillusfumigatus antigen. J Immunol 120:66, 1978. 5. Safirstein B: Allergic bronchopulmonary aspergillosis with obstmction of the upper respiratory tract. Chest 70:788, 1976. 6. Bardana E Jr: The clinical spectrum of aspergillosis. 2. Classification and description of saprophytic, allergic, and invasive variants of human disease. CRC Crit Rev Clin Lab Sci 13:85, 1980. 7. Hora J: Primary aspergillosis of the paranasal sinuses and associated areas. Laryngoscope 75:768, 1965. 8. Jahrsdoerfer R, Ejercito V, Johns M, Cantrell R, Sydnor J: Aspergillosis of the nose and paranasal sinuses. Am J Otolaryngol 1:6, 1979. 9. McGill T, Simpson G, Healy G: Fulminant aspergillosis of the nose and paranasal sinuses: a new clinical entity. Laryngoscope 90:748, 1980. 10. McGuirt W, Harrill J: Paranasal sinus aspergillosis. Laryngoscope 89~1563, 1979. 11. Veress B, Malik 0, Tayeb A, et al: Further observations on the primary paranasal Aspergillus granuloma in the Sudan. A morphological study of 46 cases. Am J Trop Med Hyg 22:765, 1973. 12. Warder F, Chikes P, Hudson W: Aspergillosis of the paranasal sinuses. Arch Otolaryngol 101:683, 1975. 13. Katzenstein A, Askin F: Surgical pathology of non-neoplastic lung disease (Major problems in pathology, vol. 13). Philadelphia, 1982, W. B. Saunders Co., pp. 124-125. 14. Berman S, Mathison D, Stevenson D, et al: Maxillary sinusitis and bronchial asthma: correlation of roentgenograms, cultures, and thermograms. J ALLERGY CLIN IMMUNOL 53:3 11, 1974. 15. Frederick J, Braude A: Anaerobic infection of the paranasai sinuses. N Engl J Med 290:135, 1974. 16. Slavin R, Cannon R, Friedman W, et al: Sinusitis and bronchial asthma. J ALLERGY CLIN IMMUNOL 66:250, 1980. 17. Irwin R, Thomas H III: Mucoid impaction of the bronchus. Diagnosis and treatment. Am Rev Respir Dis 10&955, 1973.
M.D., Scott St. Louis,
The clinical and pathologic features sinusitis are described. Most patients
MO.,
a newly
R. Sale, M.D., and and
Chicago,
Ill.
of seven cases of a newly recognized form of chronic were young adults with a history of asthma, and all had
chronic nasal polyps. Radiographically, there was opacijcation of multiple sinuses. Recurrent sinusitis was common, and several patients underwent numerous surgical drainage procedures. Histologically, a distinct mutinous material containing eosinophils, Charcot-Leyden crystals, and fungal hyphae was found in tissue resected from the sinuses. We believe that these jindings constitute a distinct clinicopathologic entity that we term allergic Aspergillus sinusitis. This condition shares similar histopathologic features with allergic bronchopulmonary aspergillosis (ABPA) but affects the paranasal sinuses rather than the lung. Implications for therapy of this form of sinusitis and its possible relationship to allergic lung diseases are discussed. (.I ALLERGY
CLIN IMMUNOL 7289-93,
1983.)
Mucoid impaction of the bronchi is one pathologic manifestation of ABPA. ‘3 * We recently encountered histologic findings indistinguishablefrom mucoid impaction of bronchi in tissue resected from the paranasalsinus of a patient undergoing surgery for chronic sinusitis. Fungal hyphae consistent with Aspergillus were also present within the impacted mutin. Similar changes have not been previously described in the paranasalsinuses,and they stimulated us to retrospectively review all tissue specimensremoved from the paranasalsinusesover a 5-year period. We identified six additional casesand compared them clinically and pathologically with examples of Aspergilfus mycetomas and nonallergic inflammatory conditions of the sinuses.We present evidence that the clinical and pathologic findings in these seven casescomprise a distinct entity possibly analogousto ABPA but occurring in the paranasalsinuses,and we
From the Department of Pathology, Washington University School of Medicine, St. Louis, MO. (A. L. A. K.), Department of Medicine, JewishHospitaIofSt. Louis, St. Louis, MO. (S. R. S.), and Northwestern University School of Medicine, Chicago, 111. (P. A. G.). Received for publication Oct. 25, 1982. Accepted for publication Jan. 27, 1983. Supported in part by the Ernest S. Bazley Grant and U.S.P.H.S. grant I 1403. Reprint requests: A. Katzenstein, M.D., Division of Surgical Pathology, University of Alabama Hospitals, 619 So. 19th St., Birmingham, AL 35233.
propose the name allergic Aspergillus sinusitis. The therapeutic implications of this condition and its possible relationship to allergic lung diseasesare discussed. MATERIALS
AND METHODS
Microscopicslideswerereviewedfrom 119 specimens surgically excised from the paranasal sinuses. These specimens included 113 consecutive cases in the Barnes Hospital SurgicalPathologyfilesfrom 1977to 1981that werecoded as acute and chronic inflammation, polyps, or mucoceles. An additional four cases coded as fungal infection between 1973 a?d 1977 were reviewed. One case was obtained from current surgical specimens at Jewish Hospital of St. Louis, and one was sent to Barnes Hospital for consultation. All slides were stained with H&E. The Gomori methenamine silver stain for fungi was used in all cases containing allergic or nonallergic mucin (see below) and in the six examples of mycetomas. The medical records were reviewed in pertinent cases, and when possible, individual patients were interviewed. Immediate cutaneous reactivity was determined in five individuals with Af and other common mold and inhalant allergens (Center Laboratories, Port Washington, N. Y .). Sera from the same patients were analyzed for precipitins to Af, total serum IgE, and IgG and IgE antibodies to Af.2, :$
RESULTS Pathologic findings Material that was indistinguishable from mucoid impaction of bronchi was found in the excised contents of the paranasalsinusesfrom nine patients. We 89
ABPA:
Allergic
H&E:
bronchopulmonary
aspergillosis
Hematoxylin-eosin stain
have termed this material ullergic mucin. It is characterized histologically by clumps of necrotic eosinophils and other cellular debris within a background of pale, eosinophilic-to-basophilic, amorphous mucin (Fig. 1). The necrotic cellular debris is frequently arranged in multilayered rows. Charcot-Leyden crystals. which appear hexagonal in cross section and bipyramidal in longitudinal section, were a consistent finding within the allergic mucin (Fig. 2, A). In seven cases thin, septate fungal hyphae that resembled Aspergillus species were found (Fig. 2, B ). The organisms occurred exclusively within the mucin, where they were scattered singly or in small clusters. There was no evidence of tissue invasion. We considered these seven patients to represent examples of allergic Aspergillus sinusitis. Eleven cases were identified in which there were varying amounts of a mutinous material that lacked the characteristic eosinophils and Charcot-Leyden crystals of allergic mucin. Sometimes neutrophils were prominent within this material, which we have termed nonullergic in$lammatory mucin. No fungi were found within this mucin. There were six examples of mycetomas of the paranasal sinuses. These lesions were characterized by densely packed, tangled masses of fungal hyphae that lacked associated allergic or nonallergic mucin. Morphologically the fungi were thin and septate and resembled Aspergillus species. There was no evidence of tissue invasion. The slides from the remaining 93 cases showed mainly nonspecific acute and chronic inflammation of sinus mucosa, inflammatory polyps, and mucoceles. They are not further discussed. Clinical
findings
Patients with allergic Aspergillus sinusitis. The clinical and radiographic features of the seven patients with allergic Aspergillus sinusitis are summarized in Table I. The mean age of these patients was 28 yr (range 13 to 48), with five between ages 13 and 25. Six patients had asthma (three in the past and three currently), and chronic nasal polyps were present in all. Three individuals were atopic. Radiographically, opacification of several or all paranasal sinuses was present. Bony erosion of the
sphenoid sinus was suspected in patient I. Chest rad!ographs were normal in all six individuals L-xamineii Three patients had a history of multlplc hrtr-gic~i procedures involving the paranasal sinuse:. Patient 2 had had five procedures in 6 years, inciudlnp hilatera? nasal antrostomies, bilateral Caldwell-Luc pr’ocedur~ (twice). a transeptal sphenoidectomy. ,md a frontai osteoplasty. Review of the tissue f‘rom these proic durea revealed allergic mucin containmg fun@ hyphae on three occasions. Patient 3 had had IO su-&al procedures on the nasal cavity and paranabal sinuses in 11 years. including five polypectomics. four Caldwell-Luc procedures. and remo! al (I!‘ a maxillary sinus cyst. Allergic mucin was found on three occasions. although hyphae were Identified in the mucin only once. Patient I had a nasal polypcctomy followed by a Caldwell-Luc procedure and ethmoidectomy 2 years later. On both occasions ailergic mucin containing hyphae was found. Patients rl,ith allergic mrrt,in \zYthout ~ir~lg!. ‘The sinus contents from two patients consisted of allergic mucin in which fungal hyphae could not be identified. These patients were 24 and 48 years old. Both had a history of asthma, chronic nasal polyps, and aspirin hypersensitivity. Opacification of several or all sinuses was seen radiographically. and chest radiographs were normal. Patients with nonallergic irzjkmmator~~ muc,in. The I I patients with nonallergic mucin formed a more heterogeneous group than the patients with allergic Aspergilllrs sinusitis. Their average age was 43 yr (range 17 to 721, and only one had a history ot asthma. In contrast to the patients with allergic .4spergillus sinusitis, more than one sinus was involved in only five individuals, one of whom had cystic fibrosis and one had diabetes with a history of prior invasive rhinocerebral mucormycosis. Bilateral sinusitis was present in the one patient with a history of asthma. Patients
with
myc’etomas
cf the paranusal
sinrcsrs~
The mean age of the six patients with mycetomas w’as 55 yr (range 29 to 65). None had a history of asthma. and a single sinus was involved in all cases (maxillary in five, sphenoid in one). Cutaneous in patients
reactivity and serobgic with aliergic &pu~~#&~
findings sinusitis
One of five patients with allergic Aspergillris sinusitis (patient 4) demonstrated immediate cutaneous activity to Af. Skin test results with several other common molds and inhalant allergens were positive in three individuals (patients 4, 5, 6). Sera were available from five patients with allergic
VOLUME NUMBER
72 1
Allergic
Aspergillus
sinusitis
91
FIG. 2. Higher-magnification photomicrographs of allergic mucin. A, Charcot-Leyden crystals that appear hexagonal in cross-section and bipyramidal in longitudinal section. (H&E; x350.) B, Thin, septate fungal hypha from a case of allergic Aspergillus sinusitis. (H&E; x480.)
FIG. 1. Low-magnification photomicrograph of allergic mucin showing clusters of darkly staining, focally necrotic eosinophils within a background of pale-staining amorphous mucin. Numerous Charcot-Leyden crystals can also be seen (arrows). (H&E; x90.)
Aspergillus sinusitis. They were obtained within several weeks of sinus surgery from patients 5,6, and 7, and in patients 3 and 4 they were obtained 4 and 1 yr after surgery, respectively. Total serum IgE levels were elevated in three individuals (patients 4, 6, 7) and precipitins to Af were detected in four (patients 4, 5, 6, 7). Serum from patients 4 and 6 demonstrated elevated IgG and IgE antibodies to Af, respectively, when compared with sera from asthmatics with cutaneous reactivity to Af but no other evidence for ABPA .3 DISCUSSION We describe seven patients with pathologic findings in the paranasal sinuses that are indistinguishable from mucoid impaction’ occurring in bronchi due to ABPA. The main feature of this lesion in both the sinuses and the bronchi is the presence of thick, inspissated mucoid material containing scattered fungal hyphae. This mucoid material, which we term allergic muck, has a distinct histologic appearance characterized by aggregates of necrotic eosinophils, nuclear
debris, free eosinophil granules, sloughed respiratory tract epithelial cells, and Charcot-Leyden crystals within an otherwise amorphous, pale eosinophilic or basophilic mutinous background. Clinically the patients with these findings comprised a relatively distinct and homogeneous group. Most were young adults with a history of asthma and nasal polyps. Radiographically, opacification of multiple paranasal sinuses was found. Three patients had recurrent sinusitis over several years and underwent numerous surgical procedures. We believe that these pathologic and clinical features constitute a previously unrecognized entity, and we have chosen the term “allergic Aspergillus sinusitis ” because of its histopathologic resemblance to ABPA .* Chest radiographs were normal in all six individuals with allergic Aspergillus sinusitis examined, and no one had a history of previous pneumonias or chest infiltrates that would suggest the possibility of ABPA. Serum precipitin reactions to Af were demonstrated in all but one patient tested, but elevated levels of both IgE and IgG antibodies to Af, which occur in ABPA, were not present .3 These serologic findings are similar to those described in patients with aspergillomas.4 We did not have serum available for comparison from patients with nonallergic mucin or mycetomas. Such studies, however, might prove helpful in the future to distinguish the groups of patients clinically. Safirstein” reported a patient with ABPA and nasal polyps who initially presented with rhinorrhea and the
92
Katzenstein
TABLE Case No. I
I. Clinical
et al.
features
of the
Age/Sex
Asthma
Atopy
I3/%1
No
No
patients
with
% Eos (total WC) NA
allergic Nasal polyps +
2
23/F
+
No
NA
+-
3
47/F
+
NO
3%(7
4
18/M
+
+
24%(5400)
+
5
27/F
+
+
3%(6100)
+
6
48/M
+
+
7%
+
7
17/F
+
No
NA
+
I oo)*
+
Aspet-gillus Sinus Opacification sphenoid: Opacitication ethmoid. Opacitication sinuses
sinusitis
films R maxillary, ?bony erosion R maxillary, frontal all paranasal
Opacification L maxillary antrum; mucosal thickening L ethmoid. sphenoid Opacification L frontal, maxillary; mucosal thickening L ethmoid Pansinusitis Opacification ethmoid,
L maxillary, sphenoid
-_ -_-__ ..---_ Surgical
procedure
R CMiwell-Luc.
ethrnoi&
cctomy , polypectomj Bilateral Caldwell-Lrri, polypectom} Bilateral Caldweil-Ltii, external ethmnidectomy L Caldwell-Luc.
Inferior turbinectomy; antrostomy
poiypectom)
L nasal
Bilateral Caldwetl-Luc. polypectomy L Caldwell-Luc, polypectomy
NA = not available; R = right; L = left. *Taking 10 mg of prednisone four times daily.
production of nasal casts. She was found radiographically to have opacified nasal sinuses.A Caldwell-Luc procedure and polypectomy were done and cultures of the excised material grew Af. Her nasal symptoms failed to improve and a lung infiltrate was noted several months after surgery. Although shehad no history of asthma, ABPA was diagnosedbecause of positive skin tests, serum precipitins to Af, and a pulmonary infiltrate with eosinophilia. Dramatic responseof the lung and nasallesionswasobtained with corticosteroid therapy. This patient likely had allergic Aspergiflus sinusitis similar to that of the patients described in this report, although the characteristic pathologic findings of this condition were not described. True infections due to Aspergillus species can occur in the paranasalsinuses,although they are not common.6-‘2 Invasive and noninvasive forms of infection have been described, and both differ clinically and pathologically from allergic Aspergilfus sinusitis. Invasive aspergillosisis characterized pathologically by tissue necrosisand a granulomatousreaction with fibrosis surrounding the organisms.*’ The infection may be relatively asymptomatic and slowly progressive ‘* R, lo or it may be a fulminant, life-threatening diseise, especially in immunocompromisedpersons.g Usually a single sinus is involved, and there is no particular association with asthma. A noninvasive form of Aspergillus infection may also occur, which is analogous to pulmonary mycetomas.12 The six mycetomasof paranasalsinusesreviewed in our study
were clearly different from casesof allergic Aspergillus sinusitis. Pathologically, they were characterized by large numbers of closely packed organismswithout accompanying allergic mucin. Clinically, the patients were older adults without evidence of asthmaor atopy, and only a single sinus was involved. It could be arguedthat the finding of fungal hyphae within allergic mucin in the paranasalsinusesreflects simply colonization of mucus by a ubiquitous fungus_ Several observations militate against this possibility. First, the histologic appearanceof allergic mucin containing fungi is identical to that of the lung lesion (mucoid impaction of bronchi), which is a welldocumentedmanifestation of ABPA. ‘CcSecond, if the fungus representednonspecific colonization, it should be present in examples of nonallergic as well as allergic mucin. We examined 11 casesof nonallergic mucin and none contained fungal hyphae. Third, although the casesof allergic Aspergillus sinusitiswere identified purely by histologic techniques, they manifested a distinct spectrumof clinical features, Similar associated, characteristic clinical features were not found in casesof nonallergic mucin or mycetomas 01 the paranasalsinuses. The role of fungal cultures in the further study of allergic Aspergillus sinusitis is questionable. The microbiology of chronic sinusitis has been extensively studied and has been found to include mainly aerobic and anaerobic bacteria with little reference to fungi. 14-16Since morphologically many of the fungi in allergic Aspergillus sinusitis appear to be degen-
VOLUME NUMBER
72 1
erating, it would not be surprising that they might be difficult to culture. The significance of the two cases of allergic mucin that did not contain fungi in our study is not clear. They may represent allergic Aspergilhs sinusitis in which, because of sampling difficulties, organisms were not identified. A similar phenomenon occurred in patient 3 who had multiple surgical procedures involving her sinuses. On one occasion, allergic mucin containing fungi was found, whereas at two other times allergic mucin lacking fungi was present. Another possible explanation for allergic mucin without fungi is that an allergen other than Aspergilfus, which may not be recognizable histologically, is responsible for the changes. Certainly, there are examples of mucoid impaction of bronchi that are of unknown etiology and cannot be attributed to ABPA.17 The optimal therapy for allergic Aspergitfw sinusitis needs to be prospectively investigated. Multiple recurrences were common in our cases after surgical drainage procedures. Dramatic improvement in both lung and nasal symptoms was obtained with corticosteroid therapy in the patient reported by Safirstein,5 and similar therapy may be useful in patients with allergic Aspergillus sinusitis. A possible relationship between allergic Aspergillus sinusitis and allergic diseases of the lung is purely speculative at this time. The association of chronic sinusitis and asthma has been known for many years, however, and improvement in asthma has been documented by some investigators after treatment of sinusitis.‘“, I6 Whether fungal antigens from the paranasal sinuses could aggravate asthmatic symptoms or whether they might have a role in the development of ABPA are unanswered questions. REFERENCES I. Katzenstein A, Liebow A, Friedman P: Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 111:197, 1975.
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Aspergillus
sinusitis
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2. Rosenberg M, Patterson R, Mintzer R, et al: Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 86~405, 1977. 3. Wang JLF, Patterson R, Rosenberg M, Roberts M, Cooper BJ: Serum IgE and IgG antibody activity against Aspergillus fumigarus as a diagnostic aid in Allergic Bronchopulmonary Aspergillosis. Am Rev Respir Dis 117:917, 1978. 4. Patterson R, Wang JLF, Roberts M, Zeiss CR: Comparison of radioimmunoassay techniques in the detection of IgE and IgG antibody activity against Aspergillusfumigatus antigen. J Immunol 120:66, 1978. 5. Safirstein B: Allergic bronchopulmonary aspergillosis with obstmction of the upper respiratory tract. Chest 70:788, 1976. 6. Bardana E Jr: The clinical spectrum of aspergillosis. 2. Classification and description of saprophytic, allergic, and invasive variants of human disease. CRC Crit Rev Clin Lab Sci 13:85, 1980. 7. Hora J: Primary aspergillosis of the paranasal sinuses and associated areas. Laryngoscope 75:768, 1965. 8. Jahrsdoerfer R, Ejercito V, Johns M, Cantrell R, Sydnor J: Aspergillosis of the nose and paranasal sinuses. Am J Otolaryngol 1:6, 1979. 9. McGill T, Simpson G, Healy G: Fulminant aspergillosis of the nose and paranasal sinuses: a new clinical entity. Laryngoscope 90:748, 1980. 10. McGuirt W, Harrill J: Paranasal sinus aspergillosis. Laryngoscope 89~1563, 1979. 11. Veress B, Malik 0, Tayeb A, et al: Further observations on the primary paranasal Aspergillus granuloma in the Sudan. A morphological study of 46 cases. Am J Trop Med Hyg 22:765, 1973. 12. Warder F, Chikes P, Hudson W: Aspergillosis of the paranasal sinuses. Arch Otolaryngol 101:683, 1975. 13. Katzenstein A, Askin F: Surgical pathology of non-neoplastic lung disease (Major problems in pathology, vol. 13). Philadelphia, 1982, W. B. Saunders Co., pp. 124-125. 14. Berman S, Mathison D, Stevenson D, et al: Maxillary sinusitis and bronchial asthma: correlation of roentgenograms, cultures, and thermograms. J ALLERGY CLIN IMMUNOL 53:3 11, 1974. 15. Frederick J, Braude A: Anaerobic infection of the paranasai sinuses. N Engl J Med 290:135, 1974. 16. Slavin R, Cannon R, Friedman W, et al: Sinusitis and bronchial asthma. J ALLERGY CLIN IMMUNOL 66:250, 1980. 17. Irwin R, Thomas H III: Mucoid impaction of the bronchus. Diagnosis and treatment. Am Rev Respir Dis 10&955, 1973.