CU R R E N T TH E R A P E U T I C RE S E A R C H 쏐 VO L UM E 64, No. 7, JUL Y/ A U GU S T 2003
Case Report Combination Therapy for Chronic Invasive Rhinocerebral Aspergillosis in a Clinically Immunocompetent Patient La´szlo´ Lujber, MD,1,2 Imre Gerlinger, PhD,3 A´da´m Kuncz, MD,2,4 and Jo´zsef Pytel, PhD1 1
Faculty of Medicine, Department of Otorhinolaryngology, Pe´cs University, Pe´cs, Hungary, 2Tawam Hospital, Abu Dhabi, United Arab Emirates, 3Department of Otolaryngology, Head and Neck Surgery, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom, and 4Faculty of Medicine, Department of Neurosurgery, Szeged University, Szeged, Hungary
ABSTRACT Background: Adequate therapy for chronic invasive rhinocerebral aspergillosis in immunocompetent patients is controversial. The incidence of the disease is high in the Sudan and the Middle East. Misinterpretation of diagnostic criteria, failure to verify tissue invasion of fungi, and a lack of understanding of the pathophysiology of various forms of fungal rhinosinusitis lead to controversies in nomenclature, diagnosis, and therapy. Objective: The aim of this report was to detail the clinical presentation and the endoscopic and imaging study findings of a patient with invasive Aspergillus rhinosinusitis with endocranial and orbital extension. This patient was treated with surgical de´bridement and a combination of antifungal drugs and immunomodulatory therapy. Methods: Endoscopic de´bridement and high-dose liposomal amphotericin B, in combination with flucytosine and immunomodulators, were used to treat this patient. Results: After treatment, the patient experienced 3 years of disease-free follow-up. Conclusion: Surgical de´bridement and high-dose systemic combined antifungal therapy with immunomodulatory drugs produced an excellent long-term result for this apparently immunocompetent patient with extensive invasive
Accepted for publication April 30, 2003. Reproduction in whole or part is not permitted.
Copyright 쑕 2003 Excerpta Medica, Inc.
doi:10.1016/S0011-393X(03)00111-5 0011-393X/03/$19.00
473
CURRENT THERAPEUTIC RESEARCH쏐
fungal rhinosinusitis with cerebral and orbital involvement. (Curr Ther Res Clin Exp. 2003;64:473–483) Copyright 쑕 2003 Excerpta Medica, Inc. Key words: amphotericin B, aspergillosis, immunocompetent, invasive, rhinocerebral.
INTRODUCTION The incidence of fungal rhinosinusitis has been grossly underestimated in the past.1,2 Both immunocompetent and immunocompromised patients are at risk. The manifestation of the disease mainly depends on the immune response of the host and is classified as acute invasive, chronic invasive, fungus ball, saprophytic colonization, or allergic fungal rhinosinusitis.3 Aspergillus fumigatus is a common fungal pathogen of the paranasal sinuses.4 Fulminating invasive types usually are seen in immunocompromised patients. The incidence of chronic invasive rhinosinusitis in individuals with no evidence of immunocompromise is high in the Sudan5 and the Middle East.6 The purpose of this report was to present the case of an apparently immunocompetent female patient with chronic invasive fungal rhinosinusitis that invaded the brain and the orbit.
PATIENT AND METHODS A 25-year-old Pakistani woman living in the United Arab Emirates (UAE) came to the emergency unit of Tawam Hospital (Abu Dhabi, UAE) in June 1999 with continuous headache, nasal discharge, and vomiting over the previous 4 months. History revealed bilateral nasal blockage and hyposmia that had begun 2 months earlier. She was not taking any medication and had no previous severe illnesses or surgeries. Clinical examination showed normal cranial nerve function, except for left partial oculomotor palsy. The patient also was slightly disoriented as to time and place. Bilateral chronic papilledema and facial asymmetry were noted. No pulmonary, urinary, or gastrointestinal disease were present. Magnetic resonance (MR) imaging of the brain (Figure 1) showed a large tumor mass in the nasal cavity and the anterior cranial fossa that infiltrated the polar and basal frontal lobe bilaterally and extended posteriorly along the planum sphenoidale to the anterior clinoid process. Posterior to the crista galli, the lamina cribrosa had been destroyed and the mass had invaded the nasal cavity, the sphenoid and bilateral ethmoid sinuses, and the orbit on both sides. The signal intensity of the tumor mass was intermediate on T1-weighted images and low on T2-weighted images. Scattered areas of enhanced signal intensity were observed. Massive brain edema was found. Missing paranasal sinus walls and remodeling and thinning of the paranasal sinus walls were seen on computed tomography (CT), together with reactive sclerosis of the sphenoid and frontal sinus bones and the planum sphenoidale. The mass had partially
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Figure 1. Magnetic resonance (MR) images of the patient before therapy. (A) Postgadolinium sagittal T1-weighted MR image of the brain showing extensive fungal involvement in the nasal cavity, sphenoid sinus, and the frontobasal brain. (B) Axial T2-weighted MR image showing spread of the disease with edema in the frontal lobe of the brain.
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destroyed the lamina papyracea. In the first week, only the medial rectal muscles were invaded, but later the fungus involved the optic nerves and the chiasm bilaterally and was adjacent to the cavernous sinus (Figure 2). Nasal endoscopy revealed anemic mucosal lining. The nasal septum was considerably thickened superiorly, and both middle turbinates were enlarged, especially on the right, with grayish-black discoloration. Under the middle turbinates and on the roof, hard, black crust was seen. Several biopsy and culture specimens were taken under a bloodless field. A fumigatus was isolated from the specimens after 1 week (Figure 3). Biopsies of the nasal mucosa showed extensive areas of noncaseating granulomatous inflammation with lymphocytes, macrophages, eosinophils, and multinucleated giant cells. Gomori’s methenamine silver stain showed multiple fungal hyphae in the submucosa, with frequent acute branching, indicating A fumigatus. Vascular invasion by fungi was not seen in the specimens. Complete blood count; baseline serum electrolyte concentrations; liver and kidney function tests; and serum glucose, total protein, albumin, and ferritin concentrations were normal, as were serum immunoglobulin (Ig)A and IgM concentrations. C-reactive protein and serum IgG concentrations were slightly elevated, as were total IgE and A fumigatus–specific IgE levels. In the peripheral blood, T- and B-lymphocyte counts were normal, but alterations were seen in T-cell subsets. CD4⫹ T-cell counts (T-helper [Th]) were low, and CD8⫹ T-cell
Figure 2. T1-weighted, postcontrast axial magnetic resonance image with fat suppression 1 week after the start of the therapy. Abnormal uptake of the paranasal sinuses, the orbital extension, and the fungi around the optic nerves are visible. Note the spread adjacent to the cavernous sinus.
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L. Lujber et al.
Figure 3. The conidial “fruiting” head of Aspergillus fumigatus resembles the font for holy water (aspergillum). (Stained with lactophenol, original magnification ×40.)
counts (T-cytotoxic) were high, giving a low CD4⫹/CD8⫹ ratio. CD16⫹ and CD56⫹ T-cell (natural killer cell) counts also were low. Neutrophil function tests of both ingestion and killing were normal compared with a control. Total complement, measured using the kinetic method, was slightly elevated. Results of rheumatoid factor and antinuclear antibody and human immunodeficiency virus antibody tests were negative. After invasive rhinocerebral aspergillosis was definitively diagnosed, treatment was started with liposomal amphotericin B (LAB)* 2 mg/kg once daily, rifampicin 600 mg once daily, dexamethasone 12 mg/d (4 mg TID), and acetazolamide† 500 mg/d (250 mg BID) to reduce intracranial pressure (Table). On day 2, endonasal endoscopic surgical de´bridement of the ethmoidal sinuses was carried out. A large mass of fungal debris was removed from the ethmoidal sinuses to reduce the fungal load. By the end of the first week of treatment, the patient’s vision and general condition suddenly deteriorated. Repeat CT scanning and MR imaging confirmed orbital and intracranial progression of the disease (Figure 2). Fungal infiltration of the optic nerves (intraorbitally and intracranially), together with the chiasma and the initial infiltration of the cavernous sinuses, were visible on the scans. The LAB dosage was increased to 4 mg/kg once daily and granulocyte–monocyte colony-stimulating factor (GM-CSF) 300 µg once daily was added to the treatment regimen. Neurosurgical intervention at this stage was not an option due to possible serious permanent *Trademark: AmBisome쑓 (Fujisawa Healthcare, Inc., Deerfield, Illinois). † Trademark: Diamox쑓 (Wyeth Pharmaceuticals, Madison, New Jersey).
477
478 4
2
6
3
7.5
6
100 µg/d
5.5
8
Gradually reduced doses
–
7.5
7
8 g/d (2 g QID)
Week
400 µg EOD
10
5
GM-CSF ⫽ granulocyte–monocyte colony-stimulating factor; IFN-γ ⫽ γ-interferon. *Trademark: AmBisome쑓 (Fujisawa Healthcare, Inc., Deerfield, Illinois). † Trademark: Rimactane쑓 (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). ‡ Trademark: Decadron쑓 (Merck, Sharp & Dohme Limited, Hoddesdon, Herts, United Kingdom). § Trademark: Diamox쑓 (Wyeth Pharmaceuticals, Madison, New Jersey). || Trademark: Leucomax쑓 (Schering-Plough Corporation, Kenilworth, New Jersey). ¶ Trademark: Immukin쑓 (Boehringer Ingelheim GmbH, Ingelheim, Germany). # Trademark: Ancobon쑓 (Roberts Pharmaceutical Corporation, Eatontown, New Jersey).
–
Flucytosine, tablet, PO#
300 µg/d 400 µg/d
–
8
4
500 mg/d (250 mg BID)
12 mg/d (4 mg TID)
600 mg/d
IFN-γ, SC injection¶
GM-CSF, SC injection||
Acetazolamide, tablet, PO§
Dexamethasone, tablet, PO‡
–
2
Liposomal amphotericin B, IV injection, mg/kg·d⫺1*
Rifampicin, capsule, PO†
1
Drug
Table. Treatment regimen.
5
10
100 µg BIW
400 µg BIW
–
5
9
–
5
11
CURRENT THERAPEUTIC RESEARCH쏐
L. Lujber et al.
iatrogenic effects. The antifungal management was modified as the LAB dosage was gradually escalated to 10 mg/kg once daily. At week 3, recombinant γ-interferon (IFN-γ) 100 µg once daily and flucytosine 8 g/d (2 g QID) were added to the treatment regimen. Rifampicin was discontinued due to its hepatotoxicity. RESULTS The patient responded well to high-dose LAB, to the addition of flucytosine, and to the immunomodulatory therapy. Continuous improvement was noted from week 5 onward as the patient’s visual disturbance and headache decreased. Repeat CT and MR scans showed evidence of clearing of the optic nerves and reduction of fungal infiltration in the anterior cranial fossa, after which doses of LAB, dexamethasone, and GM-CSF were gradually tapered. After 3 months of treatment, the patient was discharged from the hospital on IFN-γ 100 µg BIW and itraconazole 800 mg once daily for 8 months. IFN-γ treatment was stopped 4 months later. The patient has been followed up every 3 months for the past 3 years. Repeat CT and MR scans during her follow-up have revealed no intracranial fungal presence (Figure 4).
Figure 4. Postgadolinium sagittal magnetic resonance image of the patient’s brain at 3-year follow-up.
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DISCUSSION Fungal rhinosinusitis has been classified as invasive or noninvasive on the basis of tissue involvement.3 Despite the recent progress in diagnosis and therapy of invasive aspergillosis, the mortality in immunocompromised patients with cerebral involvement approaches 100%,7 whereas in an apparently normal host, it is about 13% to 50%.7,8 The chronic invasive type of the disease in immunocompetent hosts is poorly understood and reflects a geographic distribution.9 This case shares common characteristics with the invasive aspergillosis described mainly in the Sudan and the Middle East.5,6,9–11 Symptoms were nonspecific and progressed slowly (over several months); however, the disease took an aggressive clinical course in just days (deterioration occurred within hours). Nasal congestion, discharge, hyposmia, nasal pain, and headache were the first signs. The patient was unaware of her facial asymmetry.12,13 Our radiologic findings showed characteristic patterns of fungal rhinosinusitis with massive intracranial and orbital extension.14,15 Heterogeneous signal distribution with areas of high signal intensity and bony deformity on CT scanning were due to the presence of heavy metals and calcium salt precipitation in the fungal mucin. Low signal intensity on T2-weighted MR imaging was pronounced. Unlike most tumor tissues that contain free water, fungal mucin with high protein and low water concentrations showed low signal intensity on long magnetic relaxation–timed T2-weighted images. MR and CT showed fungal rhinosinusitis specifically.15 Fungal culture and biopsy specimens of nasal mucosa showed invasive fungal infection with Aspergillus, the treatment of which requires a multidisciplinary approach and teamwork. A therapeutic algorithm for invasive rhinosinusitis is surgery, systemic antifungal therapy, and reversal of the source of immunocompromise, if present.8,12,16 Radical surgical resection is said to be the cornerstone of effective eradication of fungal infection both in immunocompromised17 and immunocompetent hosts18,19; however, this approach has a high mortality and morbidity rate.8 In the presented case, it seemed futile to use radical neurosurgical intervention sufficient to completely remove such a large, noncapsulated mass with bilateral extension due to the possibility of serious permanent iatrogenic effects. We decided to perform endoscopic endonasal de´bridement to reduce the fungal load and to aerate the sinuses. During the procedure, fungal debris was removed and the mucosal lining was preserved as much as possible. At the same time, systemic antifungal therapy was started. LAB was chosen as the key antifungal agent for invasive aspergillosis in the brain and orbit. Because the patient failed to respond to the initial doses of LAB, we gradually escalated the dose. The use of high-dose LAB was based on some promising results from previous reports,20,21 which showed fewer toxic adverse effects of LAB compared with amphotericin B deoxycholate, allowing the administration of higher doses. We hypothesized that a higher dose would elevate the tissue concentration of the drug and thus increase the therapeutic effect. LAB was combined with
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flucytosine because the latter has better penetration in the cerebrospinal fluid.22,23 In vitro these agents have synergistic and antagonistic effects.23 However, their exact in vivo activity is unknown. It is not yet clear whether dose escalation or the combined use of antifungals has any benefit in the treatment of invasive fungal rhinosinusitis in immunocompetent patients, but a marked clinical improvement was observed in our case with the therapy described. GM-CSF and IFN-γ were given concomitantly, with increased doses of LAB and flucytosine. Our knowledge of pathogen-specific virulence factors and the host defense mechanism against fungal infections is incomplete. Mechanical clearance, complement system, macrophages, neutrophils, and platelets play an important role. Resistance to fungal infections is associated with increased levels of interleukin (IL)-2, IL-12, and IFN-γ.24 Although we considered our patient immunocompetent, a slight alteration in the T-cell subset was noted. Dysregulated production of Th cytokines may have contributed to the pathogenesis of this invasive aspergillosis; however, we do not have any evidence to prove that. Cytokines such as GM-CSF and IFN-γ enhance the in vivo antifungal activity of neutrophils or monocytes and macrophages.25 IFN-γ plays a role in inducing the differentiation of CD4⫹ T-cells to Th1 phenotype. The Th1 phenotype is crucial for activating the monophages against fungal pathogens (Th1 response).26 Based on the clinical improvement in this patient after immunomodulators were introduced, we believe that they helped in the patient’s recovery.
CONCLUSION Surgical de´bridement and high-dose systemic combined antifungal therapy with immunomodulatory drugs produced an excellent long-term result for this apparently immunocompetent patient with extensive invasive fungal rhinosinusitis with cerebral and orbital involvement.
REFERENCES 1. Perfect JR, Schell WA. The new fungal opportunists are coming. Clin Infect Dis. 1996;22(Suppl 2):S112–S118. 2. Pfaller MA. Epidemiology and control of fungal infections. Clin Infect Dis. 1994; 19(Suppl 1):S8–S13. 3. Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am. 2000;33: 227–235. 4. Grigoriu D, Delacre´taz J, Borelli D, eds. Medical Mycology. Toronto, Ontario, Canada: Huber; 1987:355–356. 5. Milosev B, el-Mahgoub S, Aal OA, el-Hassan AM. Primary aspergilloma of paranasal sinuses in the Sudan. A review of seventeen cases. Br J Surg. 1969;56: 132–137. 6. Dawlatly EE, Anim JT, Sowayan S, el-Hassan AY. Primary paranasal Aspergillus granuloma in Saudi Arabia. Trop Geogr Med. 1988;40:247–250.
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7. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: Review of 2,121 published cases. Rev Infect Dis. 1990;12:1147–1201. 8. Denning DW. Issues in the management of invasive aspergillosis. Ann Med Interne Paris. 1995;146:106–110. 9. Kameswaran M, al-Wadei A, Khurana P, Okafor BC. Rhinocerebral aspergillosis. J Laryngol Otol. 1992;106:981–985. 10. Sandison AT, Gentles JC, Davidson CM, et al. Aspergilloma of paranasal sinuses and the orbit in northern Sudanese. Sabouraudia. 1969;6:57–59. 11. Veress B, Malik OA, el-Tayeb AA, et al. Further observations on the primary paranasal Aspergillus granuloma in the Sudan: A morphological study of 46 cases. Am J Trop Med Hyg. 1973;22:765–772. 12. Clancy CJ, Nguyen MH. Invasive sinus aspergillosis in apparently immunocompetent hosts. J Infect. 1998;37:229–240. 13. Washburn RG, Kennedy DW, Begley MG, et al. Chronic fungal sinusitis in apparently normal hosts. Medicine Baltimore. 1988;67:231–247. 14. Stammberger H, Jakse R, Beaufort F. Aspergillosis of the paranasal sinuses: X-ray diagnosis, histopathology, and clinical aspects. Ann Otol Rhinol Laryngol. 1984;93: 251–256. 15. Zinreich SJ, Kennedy DW, Malat J, et al. Fungal sinusitis: Diagnosis with CT and MR imaging. Radiology. 1988;169:439–444. 16. Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis. 1996;23: 608–615. 17. Goering P, Berlinger NT, Weisdorf DJ. Aggressive combined modality treatment of progressive sinonasal fungal infections in immunocompromised patients. Am J Med. 1988;85:619–623. ´ r-Rahman, Jamjoom A, al-Hedaithy SS, et al. Cranial and intracranial asper18. Naim-U gillosis of sino-nasal origin: Report of nine cases. Acta Neurochir (Wien). 1996;138: 944–950. 19. Blacklock JB, Weber RS, Lee YY, Geopfert H. Transcranial resection of tumors of the paranasal sinuses and nasal cavity. J Neurosurg. 1989;71:10–15. 20. Leenders AC, Daenen S, Jansen RL, et al. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol. 1998;103:205–212. 21. Coleman JM, Hogg GG, Rosenfeld JV, Waters KD. Invasive central nervous system aspergillosis: Cure with liposomal amphotericin B, itraconazole, and radical surgery—a case report and review of the literature. Neurosurgery. 1995;36:858–863. 22. Stevens DA, Kan VL, Judson MA, et al, for the Infectious Diseases Society of America. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis. 2000; 30:696–709. 23. Denning DW, Hanson LH, Perlman AM, Stevens DA. In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents. Diagn Microbiol Infect Dis. 1992;15:21–34. 24. Roilides E, Tsaparidou S, Kadiltsoglou I, et al. Interleukin-12 enhances antifungal activity of human mononuclear phagocytes against Aspergillus fumigatus: Implications for a gamma interferon-independent pathway. Infect Immun. 1999;67:3047–3050. 25. Roilides E, Uhlig K, Venson D, et al. Enhancement of oxidative response and damage caused by human neutrophils to Aspergillus fumigatus hyphae by granulocyte colonystimulating factor and gamma interferon. Infect Immun. 1993;61:1185–1193.
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26. Gallin JI, Farber JM, Holland SM, Nutman TB. Interferon-gamma in the management of infectious diseases. Ann Intern Med. 1995;123:216–224.
Address correspondence to: La´szlo´ Lujber, MD Tawam Hospital PO Box 15258 Al-Ain Abu Dhabi UAE E-mail: [email protected]
483
Case Report Combination Therapy for Chronic Invasive Rhinocerebral Aspergillosis in a Clinically Immunocompetent Patient La´szlo´ Lujber, MD,1,2 Imre Gerlinger, PhD,3 A´da´m Kuncz, MD,2,4 and Jo´zsef Pytel, PhD1 1
Faculty of Medicine, Department of Otorhinolaryngology, Pe´cs University, Pe´cs, Hungary, 2Tawam Hospital, Abu Dhabi, United Arab Emirates, 3Department of Otolaryngology, Head and Neck Surgery, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom, and 4Faculty of Medicine, Department of Neurosurgery, Szeged University, Szeged, Hungary
ABSTRACT Background: Adequate therapy for chronic invasive rhinocerebral aspergillosis in immunocompetent patients is controversial. The incidence of the disease is high in the Sudan and the Middle East. Misinterpretation of diagnostic criteria, failure to verify tissue invasion of fungi, and a lack of understanding of the pathophysiology of various forms of fungal rhinosinusitis lead to controversies in nomenclature, diagnosis, and therapy. Objective: The aim of this report was to detail the clinical presentation and the endoscopic and imaging study findings of a patient with invasive Aspergillus rhinosinusitis with endocranial and orbital extension. This patient was treated with surgical de´bridement and a combination of antifungal drugs and immunomodulatory therapy. Methods: Endoscopic de´bridement and high-dose liposomal amphotericin B, in combination with flucytosine and immunomodulators, were used to treat this patient. Results: After treatment, the patient experienced 3 years of disease-free follow-up. Conclusion: Surgical de´bridement and high-dose systemic combined antifungal therapy with immunomodulatory drugs produced an excellent long-term result for this apparently immunocompetent patient with extensive invasive
Accepted for publication April 30, 2003. Reproduction in whole or part is not permitted.
Copyright 쑕 2003 Excerpta Medica, Inc.
doi:10.1016/S0011-393X(03)00111-5 0011-393X/03/$19.00
473
CURRENT THERAPEUTIC RESEARCH쏐
fungal rhinosinusitis with cerebral and orbital involvement. (Curr Ther Res Clin Exp. 2003;64:473–483) Copyright 쑕 2003 Excerpta Medica, Inc. Key words: amphotericin B, aspergillosis, immunocompetent, invasive, rhinocerebral.
INTRODUCTION The incidence of fungal rhinosinusitis has been grossly underestimated in the past.1,2 Both immunocompetent and immunocompromised patients are at risk. The manifestation of the disease mainly depends on the immune response of the host and is classified as acute invasive, chronic invasive, fungus ball, saprophytic colonization, or allergic fungal rhinosinusitis.3 Aspergillus fumigatus is a common fungal pathogen of the paranasal sinuses.4 Fulminating invasive types usually are seen in immunocompromised patients. The incidence of chronic invasive rhinosinusitis in individuals with no evidence of immunocompromise is high in the Sudan5 and the Middle East.6 The purpose of this report was to present the case of an apparently immunocompetent female patient with chronic invasive fungal rhinosinusitis that invaded the brain and the orbit.
PATIENT AND METHODS A 25-year-old Pakistani woman living in the United Arab Emirates (UAE) came to the emergency unit of Tawam Hospital (Abu Dhabi, UAE) in June 1999 with continuous headache, nasal discharge, and vomiting over the previous 4 months. History revealed bilateral nasal blockage and hyposmia that had begun 2 months earlier. She was not taking any medication and had no previous severe illnesses or surgeries. Clinical examination showed normal cranial nerve function, except for left partial oculomotor palsy. The patient also was slightly disoriented as to time and place. Bilateral chronic papilledema and facial asymmetry were noted. No pulmonary, urinary, or gastrointestinal disease were present. Magnetic resonance (MR) imaging of the brain (Figure 1) showed a large tumor mass in the nasal cavity and the anterior cranial fossa that infiltrated the polar and basal frontal lobe bilaterally and extended posteriorly along the planum sphenoidale to the anterior clinoid process. Posterior to the crista galli, the lamina cribrosa had been destroyed and the mass had invaded the nasal cavity, the sphenoid and bilateral ethmoid sinuses, and the orbit on both sides. The signal intensity of the tumor mass was intermediate on T1-weighted images and low on T2-weighted images. Scattered areas of enhanced signal intensity were observed. Massive brain edema was found. Missing paranasal sinus walls and remodeling and thinning of the paranasal sinus walls were seen on computed tomography (CT), together with reactive sclerosis of the sphenoid and frontal sinus bones and the planum sphenoidale. The mass had partially
474
L. Lujber et al.
Figure 1. Magnetic resonance (MR) images of the patient before therapy. (A) Postgadolinium sagittal T1-weighted MR image of the brain showing extensive fungal involvement in the nasal cavity, sphenoid sinus, and the frontobasal brain. (B) Axial T2-weighted MR image showing spread of the disease with edema in the frontal lobe of the brain.
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CURRENT THERAPEUTIC RESEARCH쏐
destroyed the lamina papyracea. In the first week, only the medial rectal muscles were invaded, but later the fungus involved the optic nerves and the chiasm bilaterally and was adjacent to the cavernous sinus (Figure 2). Nasal endoscopy revealed anemic mucosal lining. The nasal septum was considerably thickened superiorly, and both middle turbinates were enlarged, especially on the right, with grayish-black discoloration. Under the middle turbinates and on the roof, hard, black crust was seen. Several biopsy and culture specimens were taken under a bloodless field. A fumigatus was isolated from the specimens after 1 week (Figure 3). Biopsies of the nasal mucosa showed extensive areas of noncaseating granulomatous inflammation with lymphocytes, macrophages, eosinophils, and multinucleated giant cells. Gomori’s methenamine silver stain showed multiple fungal hyphae in the submucosa, with frequent acute branching, indicating A fumigatus. Vascular invasion by fungi was not seen in the specimens. Complete blood count; baseline serum electrolyte concentrations; liver and kidney function tests; and serum glucose, total protein, albumin, and ferritin concentrations were normal, as were serum immunoglobulin (Ig)A and IgM concentrations. C-reactive protein and serum IgG concentrations were slightly elevated, as were total IgE and A fumigatus–specific IgE levels. In the peripheral blood, T- and B-lymphocyte counts were normal, but alterations were seen in T-cell subsets. CD4⫹ T-cell counts (T-helper [Th]) were low, and CD8⫹ T-cell
Figure 2. T1-weighted, postcontrast axial magnetic resonance image with fat suppression 1 week after the start of the therapy. Abnormal uptake of the paranasal sinuses, the orbital extension, and the fungi around the optic nerves are visible. Note the spread adjacent to the cavernous sinus.
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L. Lujber et al.
Figure 3. The conidial “fruiting” head of Aspergillus fumigatus resembles the font for holy water (aspergillum). (Stained with lactophenol, original magnification ×40.)
counts (T-cytotoxic) were high, giving a low CD4⫹/CD8⫹ ratio. CD16⫹ and CD56⫹ T-cell (natural killer cell) counts also were low. Neutrophil function tests of both ingestion and killing were normal compared with a control. Total complement, measured using the kinetic method, was slightly elevated. Results of rheumatoid factor and antinuclear antibody and human immunodeficiency virus antibody tests were negative. After invasive rhinocerebral aspergillosis was definitively diagnosed, treatment was started with liposomal amphotericin B (LAB)* 2 mg/kg once daily, rifampicin 600 mg once daily, dexamethasone 12 mg/d (4 mg TID), and acetazolamide† 500 mg/d (250 mg BID) to reduce intracranial pressure (Table). On day 2, endonasal endoscopic surgical de´bridement of the ethmoidal sinuses was carried out. A large mass of fungal debris was removed from the ethmoidal sinuses to reduce the fungal load. By the end of the first week of treatment, the patient’s vision and general condition suddenly deteriorated. Repeat CT scanning and MR imaging confirmed orbital and intracranial progression of the disease (Figure 2). Fungal infiltration of the optic nerves (intraorbitally and intracranially), together with the chiasma and the initial infiltration of the cavernous sinuses, were visible on the scans. The LAB dosage was increased to 4 mg/kg once daily and granulocyte–monocyte colony-stimulating factor (GM-CSF) 300 µg once daily was added to the treatment regimen. Neurosurgical intervention at this stage was not an option due to possible serious permanent *Trademark: AmBisome쑓 (Fujisawa Healthcare, Inc., Deerfield, Illinois). † Trademark: Diamox쑓 (Wyeth Pharmaceuticals, Madison, New Jersey).
477
478 4
2
6
3
7.5
6
100 µg/d
5.5
8
Gradually reduced doses
–
7.5
7
8 g/d (2 g QID)
Week
400 µg EOD
10
5
GM-CSF ⫽ granulocyte–monocyte colony-stimulating factor; IFN-γ ⫽ γ-interferon. *Trademark: AmBisome쑓 (Fujisawa Healthcare, Inc., Deerfield, Illinois). † Trademark: Rimactane쑓 (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). ‡ Trademark: Decadron쑓 (Merck, Sharp & Dohme Limited, Hoddesdon, Herts, United Kingdom). § Trademark: Diamox쑓 (Wyeth Pharmaceuticals, Madison, New Jersey). || Trademark: Leucomax쑓 (Schering-Plough Corporation, Kenilworth, New Jersey). ¶ Trademark: Immukin쑓 (Boehringer Ingelheim GmbH, Ingelheim, Germany). # Trademark: Ancobon쑓 (Roberts Pharmaceutical Corporation, Eatontown, New Jersey).
–
Flucytosine, tablet, PO#
300 µg/d 400 µg/d
–
8
4
500 mg/d (250 mg BID)
12 mg/d (4 mg TID)
600 mg/d
IFN-γ, SC injection¶
GM-CSF, SC injection||
Acetazolamide, tablet, PO§
Dexamethasone, tablet, PO‡
–
2
Liposomal amphotericin B, IV injection, mg/kg·d⫺1*
Rifampicin, capsule, PO†
1
Drug
Table. Treatment regimen.
5
10
100 µg BIW
400 µg BIW
–
5
9
–
5
11
CURRENT THERAPEUTIC RESEARCH쏐
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iatrogenic effects. The antifungal management was modified as the LAB dosage was gradually escalated to 10 mg/kg once daily. At week 3, recombinant γ-interferon (IFN-γ) 100 µg once daily and flucytosine 8 g/d (2 g QID) were added to the treatment regimen. Rifampicin was discontinued due to its hepatotoxicity. RESULTS The patient responded well to high-dose LAB, to the addition of flucytosine, and to the immunomodulatory therapy. Continuous improvement was noted from week 5 onward as the patient’s visual disturbance and headache decreased. Repeat CT and MR scans showed evidence of clearing of the optic nerves and reduction of fungal infiltration in the anterior cranial fossa, after which doses of LAB, dexamethasone, and GM-CSF were gradually tapered. After 3 months of treatment, the patient was discharged from the hospital on IFN-γ 100 µg BIW and itraconazole 800 mg once daily for 8 months. IFN-γ treatment was stopped 4 months later. The patient has been followed up every 3 months for the past 3 years. Repeat CT and MR scans during her follow-up have revealed no intracranial fungal presence (Figure 4).
Figure 4. Postgadolinium sagittal magnetic resonance image of the patient’s brain at 3-year follow-up.
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DISCUSSION Fungal rhinosinusitis has been classified as invasive or noninvasive on the basis of tissue involvement.3 Despite the recent progress in diagnosis and therapy of invasive aspergillosis, the mortality in immunocompromised patients with cerebral involvement approaches 100%,7 whereas in an apparently normal host, it is about 13% to 50%.7,8 The chronic invasive type of the disease in immunocompetent hosts is poorly understood and reflects a geographic distribution.9 This case shares common characteristics with the invasive aspergillosis described mainly in the Sudan and the Middle East.5,6,9–11 Symptoms were nonspecific and progressed slowly (over several months); however, the disease took an aggressive clinical course in just days (deterioration occurred within hours). Nasal congestion, discharge, hyposmia, nasal pain, and headache were the first signs. The patient was unaware of her facial asymmetry.12,13 Our radiologic findings showed characteristic patterns of fungal rhinosinusitis with massive intracranial and orbital extension.14,15 Heterogeneous signal distribution with areas of high signal intensity and bony deformity on CT scanning were due to the presence of heavy metals and calcium salt precipitation in the fungal mucin. Low signal intensity on T2-weighted MR imaging was pronounced. Unlike most tumor tissues that contain free water, fungal mucin with high protein and low water concentrations showed low signal intensity on long magnetic relaxation–timed T2-weighted images. MR and CT showed fungal rhinosinusitis specifically.15 Fungal culture and biopsy specimens of nasal mucosa showed invasive fungal infection with Aspergillus, the treatment of which requires a multidisciplinary approach and teamwork. A therapeutic algorithm for invasive rhinosinusitis is surgery, systemic antifungal therapy, and reversal of the source of immunocompromise, if present.8,12,16 Radical surgical resection is said to be the cornerstone of effective eradication of fungal infection both in immunocompromised17 and immunocompetent hosts18,19; however, this approach has a high mortality and morbidity rate.8 In the presented case, it seemed futile to use radical neurosurgical intervention sufficient to completely remove such a large, noncapsulated mass with bilateral extension due to the possibility of serious permanent iatrogenic effects. We decided to perform endoscopic endonasal de´bridement to reduce the fungal load and to aerate the sinuses. During the procedure, fungal debris was removed and the mucosal lining was preserved as much as possible. At the same time, systemic antifungal therapy was started. LAB was chosen as the key antifungal agent for invasive aspergillosis in the brain and orbit. Because the patient failed to respond to the initial doses of LAB, we gradually escalated the dose. The use of high-dose LAB was based on some promising results from previous reports,20,21 which showed fewer toxic adverse effects of LAB compared with amphotericin B deoxycholate, allowing the administration of higher doses. We hypothesized that a higher dose would elevate the tissue concentration of the drug and thus increase the therapeutic effect. LAB was combined with
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flucytosine because the latter has better penetration in the cerebrospinal fluid.22,23 In vitro these agents have synergistic and antagonistic effects.23 However, their exact in vivo activity is unknown. It is not yet clear whether dose escalation or the combined use of antifungals has any benefit in the treatment of invasive fungal rhinosinusitis in immunocompetent patients, but a marked clinical improvement was observed in our case with the therapy described. GM-CSF and IFN-γ were given concomitantly, with increased doses of LAB and flucytosine. Our knowledge of pathogen-specific virulence factors and the host defense mechanism against fungal infections is incomplete. Mechanical clearance, complement system, macrophages, neutrophils, and platelets play an important role. Resistance to fungal infections is associated with increased levels of interleukin (IL)-2, IL-12, and IFN-γ.24 Although we considered our patient immunocompetent, a slight alteration in the T-cell subset was noted. Dysregulated production of Th cytokines may have contributed to the pathogenesis of this invasive aspergillosis; however, we do not have any evidence to prove that. Cytokines such as GM-CSF and IFN-γ enhance the in vivo antifungal activity of neutrophils or monocytes and macrophages.25 IFN-γ plays a role in inducing the differentiation of CD4⫹ T-cells to Th1 phenotype. The Th1 phenotype is crucial for activating the monophages against fungal pathogens (Th1 response).26 Based on the clinical improvement in this patient after immunomodulators were introduced, we believe that they helped in the patient’s recovery.
CONCLUSION Surgical de´bridement and high-dose systemic combined antifungal therapy with immunomodulatory drugs produced an excellent long-term result for this apparently immunocompetent patient with extensive invasive fungal rhinosinusitis with cerebral and orbital involvement.
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Address correspondence to: La´szlo´ Lujber, MD Tawam Hospital PO Box 15258 Al-Ain Abu Dhabi UAE E-mail: [email protected]
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