Discussions on Fungal Taxonomy and Nomenclature of Allergic Fungal Rhinosinusitis

Romanian Journal of Rhinology, Vol. 3, No. 11, July - September 2013 LITERATURE REVIEW Discussions on fungal taxonomy and nomenclature of allergic fungal rhinosinusitis

Florin-Dan Popescu Department of Allergology, “Nicolae Malaxa” Clinical Hospital, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

ABSTRACT

There is a significant debate regarding the role of fungi in chronic rhinosinusitis and whether allergic fungal rhinosinusitis truly represents an allergic subtype. The diverse nomenclature and heterogeneous taxonomy of fungi involved in the etiopathogenesis of this entity is important to be discussed in order to clarify the organisms detected and involved in this complex disease. KEYWORDS: fungi, allergic fungal rhinosinusitis

INTRODUCTION flammatory cascade in AFRS is a multifunctional event, requiring the simultaneous occurrence of IgE- Fungal diseases of the nose and sinuses include a mediated sensitivity, specific T-cell HLA receptor ex- diverse spectrum of disease1. Although confusion pression and exposure to specific fungi4. Early recog- exists regarding fungal rhinosinusitis (FRS) classifi- nition of AFRS may be facilitated by screening pa- cation, a commonly accepted system divides FRS into tients with polypoid chronic rhinosinusitis or CRS invasive and noninvasive diseases based on histo- with nasal polyps (CRSwNP) patients for serum spe- pathological evidence of tissue invasion by fungi. cific IgE to molds5. Such specific IgE antibodies are The noninvasive diseases include saprophytic fungal also detectable in nasal lavage fluid and eosinophilic infestation, fungal ball and fungus-related eosinophi- mucin. Sinus mucosa homogenates may be assessed lic FRS (EFRS) that includes allergic fungal rhinosi- for IgE localization by immunohistochemistry and nusitis (AFRS). for antigen-specific IgE to fungal antigens by fluores- cent enzyme immunoassay6. More fungal specific IgE is expressed in inferior turbinate and sinus tissues of ALLERGIC FUNGAL RHINOSINUSITIS AND AFRS patients, compared with patients with CRS FUNGAL TAXONOMY without nasal polyps7. Compared with patients with only nasal polyps, AFRS patients have significantly AFRS is a type of chronic rhinosinusitis (CRS) in elevated serum levels of fungus-specific IgG. Elevated which patients classically exhibit nasal polyps, IgE- levels of fungal-specific IgG3 seem to be a consistent mediated hypersensitivity, characteristic findings on finding8, 9. In the etiopathogenesis of AFRS addi- computed tomography scans, eosinophilic mucin tional data have involved also non-IgE and cellular- and positive fungal stain2,3. Initiation of the in- mediated pathways, including fungal antigens stimu-

Corresponding author: Florin-Dan Popescu, MD, PhD, Associate Professor, e-mail: [email protected] 166 Romanian Journal of Rhinology, Vol. 3, No. 11, July - September 2013 lated T-cell activation with induction of a predomi- regarding the causative organisms involved in 10 19 nantly T helper 2 (Th2) immune response . AFRS AFRS ; usually fungi from the subkingdom Dikarya, and CRSwNP have increased numbers of local den- belonging to the phylum Ascomycota, and sometimes dritic cells (DC) displaying costimulatory molecules, to the phylum Basidiomycota. Ascomycetes are char- DC chemoattractants, and their corresponding re- acterized by the ascus, a microscopic sexual struc- ceptors in the sinus mucosa versus controls. These ture in which ascospores are formed. Phylum Basid- differences may explain the mechanism for the in- iomycota is characterized by reproductive spores 11 creased numbers of DC with a Th2-skewed profile . called basidiospores, produced by specialized fun- There is a significant debate regarding the role of gal cells called basidia20. fungi in CRSwNP and whether the diagnostic group The most common fungi associated with AFRS21-23 of AFRS truly represents a unique disease. There is a are species belonging to the phylum Ascomycota, the subset of patients defined by the classic Bent-Kuhn classes: criteria for AFRS who demonstrate some phenotypic Dothideomycetes, family Pleosporaceae: differences when compared to other CRSwNP pa- • Bipolaris species (spp.), tients. These criteria consist of the following: nasal • Cochliobolus lunatus (Curvularia lunata) polyposis, fungi on staining, eosinophilic mucin • Alternaria alternata, without fungal invasion into sinus tissue, type I hy- • Cladosporium spp., persensitivity to fungi and characteristic radiological • Setosphaeria rostrata, findings with soft tissue differential densities on CT Sordariomycetes, order Hypocreales: scanning. Many issues remain unclear related to the • Sarocladium kiliense, existence of significant underlying immunologic dif- • Fusarium spp. ferences between AFRS and other forms of CRSwNP, Eurothiomycetes, family Trichocomaceae: the relevance and immunologic role of fungi or fun- • Aspergillus spp., gal specific IgE in the pathophysiology of AFRS12. • Penicillium spp. Although there are several potential deficits revealed From the phylum Basidiomycota, class Agaricomyce- in the innate and probably also in the acquired im- tes, Schizophyllum commune (synonyms: Daedalea com- munity of CRS patients that might reduce or modify mune, Merulius communis, Scaphophorum agaricoides, their ability to react to fungi, there are not many data Agaricus alneus) may cause AFRS and may be misdiag- to suggest a clear causative role for fungi in CRS with nosed as Aspergillus, because the fungus is difficult to or without nasal polyps. However, fungi might have be identified in culture and the histopathological a disease-modifying role13. findings are similar for these fungi. Allergic fungal rhinosinusitis, as a phenotype of Bipolaris spicifera, a fungal plant pathogen, is often CRSwNP, characterized by IgE-mediated hypersen- named as one of its synonyms, Drechslera spicifera, Hel- sitivity to fungi, eosinophilic mucin with fungal hy- minthosporium spiciferum, Cochliobolus spicifer, Pseudoco- phae in sinus secretions, and propensity for muco- chliobolus spicifer which can lead to confusion. cele formation and bone erosion9, is a noninvasive Bipolaris hawaiiensis has also similar synonyms, form of FRS with a prevalence of 6-9 % among such as Drechslera hawaiiensis, Helminthosporium ha- all rhinosinusitis cases requiring surgery. waiiense. The fungi causing AFRS have a great diversity and Cochliobolus lunatus, another fungal plant patho- regional variation in the incidence of AFS has been gen, was previously named Curvularia lunata. Other reported worldwide14. synonyms are Acrothecium lunatum and Pseudoco- Diagnosis of AFRS is complicated because of the chliobolus lunatus. presence of fungi on mucosal surfaces of sinonasal Alternaria alternata has several synonyms, such as passages. Fungal load colonization may modify the Alternaria tenuis, Alternaria rugosa and Torula alternata. classic eosinophilic inflammation in AFRS15,16. With Setosphaeria rostrata has many synonyms: Drechslera novel laboratory techniques, in patients with CRS the halodes, Exserohilum halodes, Helminthosporium halodes amount of positive fungal cultures increased signifi- var. tritici, Setomelanomma rostrata and others. cantly17. In patients with AFRS a modern approach Sarocladium kiliense is also named Acremonium may include the detection of fungi in sinus aspirate kiliense, Acremonium incoloratum or Cephalosporium by fungal cultures, the detection of fungal DNA by acremonium. polymerase chain reaction (PCR) assay and the mea- Penicillium expansum, Aspergillus flavus and Aspergil- suring of fungal-specific IgE levels in sinus aspirate lus niger are also involved etiologically in AFRS. (not always accompanied with fungal growth)18. Species of Bipolaris, Curvularia and Aspergillus seem The history of the fungal nomenclature is an im- to be the prevalent isolated species in AFRS. portant source of confusion. Discussion on the tax- Detection of fungi in sinus aspirate by fungal cul- onomy of fungi is useful to provide information tures is important, because the presence of fungi in Popescu Discussions on fungal taxonomy and nomenclature of allergic fungal rhinosinusitis 167

anatomic subsites of allergic fungal rhinosinusitis patients. Otolaryn- the allergic mucin is a significant finding. Dematia- gol Head Neck Surg., 2009;141(1):97-103. ceous fungi are naturally pigmented molds whose 8. Ryan M.W., Marple B.F. - Allergic fungal rhinosinusitis: diagnosis and hyphae and conidia contain melanin. Fontana-Mas- management. Curr Opin Otolaryngol Head Neck Surg., son silver stain is useful to demonstrate pigments in 2007;15(1):18-22. dematiaceous organisms, such as Bipolaris and Curvu- 9. Ryan M.W. - Allergic fungal rhinosinusitis. Otolaryngol Clin N Am., laria. These dematiaceous fungi are associated with 2011;44:697-710. eosinophilia and allergic rhinosinusitis or allergic 10. Luong A., Davis L.S., Marple B.F. - Peripheral blood mononuclear cells from allergic fungal rhinosinusitis adults express a Th cytokine re- bronchopulmonary mycosis. Septate hyaline hyphae 2 of filamentous fungi can represent species of Aspergil- sponse to fungal antigens. Am J Rhinol Allergy., 2009;23(3):281-287. lus, Fusarium or Acremonium. Squash cytology of the 11. Ayers C.M., Schlosser R.J., O’Connell B.P., Atkinson C., Mulligan R.M., Casey S.E., Bleier B.S., Wang E.W., Sansoni E.R., Kuhlen J.L., paranasal sinus contents is useful for proving the Mulligan J.K. - Increased presence of dendritic cells and dendritic cell presence of fungi. Histopathologic sections from tis- chemokines in the sinus mucosa of chronic rhinosinusitis with nasal sue samples containing mucin from the paranasal polyps and allergic fungal rhinosinusitis. Int Forum Allergy Rhinol., sinuses obtained by endoscopic sinus surgery may re- 2011;1(4):296-302. veal hyphal elements within the allergic mucin but 12. Fokkens W.J., Lund V.J., Mullol J., Bachert C., Alobid I., Baroody F., no tissue invasion. Detection of fungal surface anti- Cohen N., Cervin A., Douglas R., Gevaert P., Georgalas C., Goossens gens by enzyme linked immunosorbent assays H., Harvey R., Hellings P., Hopkins C., Jones N., Joos G., Kalogjera L., (ELISA) with monoclonal antibodies and immuno- Kern B., Kowalski M., Price D., Riechelmann H., Schlosser R., Senior fluorescence microscopy (IMF) are useful to distin- B., Thomas M., Toskala E., Voegels R., Wang de Y., Wormald P.J. - guish between the fungi. The detection of fungal European Position Paper on Rhinosinusitis and Nasal Polyps 2012. DNA by polymerase chain reaction (PCR) assay is a Rhinol Suppl., 2012;(23)1-298. PubMed PMID: 22764607. 13. Fokkens W.J., van Drunen C., Georgalas C., Ebbens F. - Role of fungi superior method of detecting fungal growth versus in pathogenesis of chronic rhinosinusitis: the hypothesis rejected. fungal cultures. Curr Opin Otolaryngol Head Neck Surg., 2012;20(1):19-23. 14. Bakhshaee M., Fereidouni M., Mohajer M.N., Majidi M.R., Azad F.J., Moghiman T. - The prevalence of allergic fungal rhinosinusitis in si- CONCLUSIONS nonasal polyposis. Eur Arch Otorhinolaryngol., 2013 Mar 28. [Epub ahead of print] PubMed PMID: 23536137. All the biological and clinical data presented 15. Ragab A., Samaka R.M. - Immunohistochemical dissimilarity between above21-32, reveal the fact that the diverse nomencla- allergic fungal and nonfungal chronic rhinosinusitis. Am J Rhinol ture and heterogeneous taxonomy of fungi involved Allergy., 2013;27(3):168-176. in the etiopathogenesis of AFRS is important to be dis- 16. Ragab A., Samaka R.M., Salem M. - Impact of fungal load on diagnosis cussed in order to clarify the organisms detected and and outcome of allergic fungal rhinosinusitis. Eur Arch Otorhino- laryngol. 2013 Apr 9. [Epub ahead of print] PubMed PMID: 23568040. involved in this complex disease. 17. Braun H., Buzina W., Freudenschuss K., Beham A., Stammberger H. - Eosinophilic fungal rhinosinusitis: a common disorder in Europe? Laryngoscope., 2003;113(2):264-269. REFERENCES 18. El-Morsy S.M., Khafagy Y.W., El-Naggar M.M., Beih A.A. - Allergic fungal rhinosinusitis: detection of fungal DNA in sinus aspirate using 1. Chang C., Gershwin M.E., Thompson G.R. 3rd. - Fungal disease of the polymerase chain reaction. J Laryngol Otol., 2010;124(2):152-160. nose and sinuses: an updated overview. Curr Allergy Asthma Rep., 19. Lutzoni F., Kauff F., Cox C.J., McLaughlin D., Celio G., Dentinger B., 2013;13(2):152-161. et al. - Assembling the fungal tree of life: progress, classification, and 2. Laury A.M., Wise S.K. - Chapter 7: Allergic fungal rhinosinusitis. Am evolution of subcellular traits. American Journal of Botany., J Rhinol Allergy., 2013;27 Suppl 1:26-27. 2004;91:1446-1480. 3. Silva M.P., Baroody F.M. - Allergic fungal rhinosinusitis. Ann Allergy 20. Rivera-Mariani F.E., Nazario-Jiménez S., López-Malpica F., Bolaños- Asthma Immunol., 2013;110(4):217-222. Rosero B. - Sensitization to airborne ascospores, basidiospores, and 4. Chakrabarti A., Denning D.W., Ferguson B.J., Ponikau J., Buzina W., fungal fragments in allergic rhinitis and asthmatic subjects in San Kita H., Marple B., Panda N., Vlaminck S., Kauffmann-Lacroix C., Das Juan, Puerto Rico. Int Arch Allergy Immunol., 2011;155(4):322-334. A., Singh P., Taj-Aldeen S.J., Kantarcioglu A.S., Handa K.K., Gupta A., 21. Manning S.C., Holman M. - Further evidence for allergic pathophysi- Thungabathra M., Shivaprakash M.R., Bal A., Fothergill A., Radotra ology in allergic fungal sinusitis. Laryngoscope., 1998;108(10):1485- B.D. - Fungal rhinosinusitis: a categorization and definitional schema 1496. addressing current controversies. Laryngoscope., 2009;119(9):1809- 22. Braun H., Buzina W., Freudenschuss K., Beham A., Stammberger H. 1818. - Eosinophilic fungal rhinosinusitis: a common disorder in Europe? 5. Stewart A.E., Hunsaker D.H. - Fungus-specific IgG and IgE in allergic Laryngoscope., 2003;113:264-269. fungal rhinosinusitis. Otolaryngol Head Neck Surg., 2002;127(4):324-32. 23. Ahmed M.K., Ishino T., Takeno S., Hirakawa K. - Bilateral allergic 6. Wise S.K., Ahn C.N., Lathers D.M., Mulligan R.M., Schlosser R.J. - fungal rhinosinusitis caused by Schizophillum commune and Asper- Antigen-specific IgE in sinus mucosa of allergic fungal rhinosinusitis gillus niger. A case report. Rhinology., 2009;47(2):217-221. patients. Am J Rhinol., 2008;22(5):451-456. 24. McGinnis M.R., Campbell G., Gourley W.K., Lucia H.L. - Phaeohy- 7. Ahn C.N., Wise S.K., Lathers D.M., Mulligan R.M., Harvey R.J., phomycosis caused by Bipolaris spicifera: an informative case. Eur J Schlosser R.J. - Local production of antigen-specific IgE in different Epidemiol., 1992;8(3):383-386. 168 Romanian Journal of Rhinology, Vol. 3, No. 11, July - September 2013

25. Karpovich-Tate N., Dewey F.M., Smith E.J., Lund V.J., Gurr P.A., Gurr lergic fungal sinusitis caused by Bipolaris spicifera and Schizophyllum S.J. - Detection of fungi in sinus fluid of patients with allergic fungal commune. Med Mycol., 2007;45(6):559-564. rhinosinusitis. Acta Otolaryngol., 2000;120(2):296-302. 29. Elmorsy S., El-Naggar M.M., Abdel aal S.M., Abou-elela M.A. - Sinus 26. Brandt M.E., Warnock D.W. - Epidemiology, clinical manifestations, aspirates in chronic rhinosinusitis: fungal colonization of paranasal si- and therapy of infections caused by dematiaceous fungi. J Che- nuses, evaluation of ICAM-1 and IL-8 and studying of immunological mother., 2003;15 Suppl 2:36-47. effect of long-term macrolide therapy. Rhinology., 2010;48(3):312-317. 27. Taj-Aldeen S.J., Hilal A.A., Schell W.A. - Allergic fungal rhinosinusitis: 30. Guarner J., Brandt M.E. - Histopathologic diagnosis of fungal infecti- a report of 8 cases. Am J Otolaryngol., 2004;25(3):213-218. ons in the 21st century. Clin Microbiol Rev., 2011;24(2):247-280. 28. Taguchi K., Oharaseki T., Yokouchi Y., Kawabata T., Wakayama M., 31. www.speciesfungorum.org Ogoshi T., Iwabuchi S., Shibuya K., Nishimura K., Takahashi K. - Al- 32. www.ncbi.nlm.nih.gov/taxonomy