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Acquired immunodeficiency syndrome with massive Aspergillus fumigatus infection
CLINICAL PATHOLOGY Acquired immunodeficiency syndrome with massive Aspergillus fumigatus infection E. MALIK DIOR MD, PATRICIAA. SCHACHERN, BS,and MICHAEL M. PAPARELLA,MD, Minneapolis, Minnesota, and Dakar, Senegal
S i n c e the first report of AIDS in 1980, the medical community and the whole of society have been challenged by the various aspects of this disease. Statistics from the Center for Disease Control and Prevention (CDC) in Atlanta, Georgia, showed 401,749 cases of AIDS in the United States as of June 1994, comprising all age groups and a wide variety of clinical aspects. 1 Because of the polysystemic nature of this illness, patients can have clinical features that shape-shift in relation to opportunistic infections, tumors, viruses, and side effects from the various drugs used to relieve their conditions. Clinical aspects of this syndrome also vary according to the current status of each particular patient's immune system. Therefore the myriad of challenges brought forth by this disease encompass the entire medical community. Either for primary care or when referred for evaluation, 40% of patients with AIDS will consult an otolaryngologist, who must deal with opportunistic infections, side effects of several drugs, tumors, or other viral infections. 2 These patients' common otologic symptoms include vertigo, otalgia, otorrhea, and hearing loss. Many investigators have reported otologic manifestations in patients with AIDS, but most such studies have been clinical. 2-8 Although insight into the patho-
From the University of Minnesota Otitis Media Research Center, Department of Otolaryngology(Drs. Diop and Paparella and Ms. Schachern), University of Minnesota Medical School; The Minnesota Ear, Head and Neck Clinic (Dr. Paparella); and the Department of Otolaryngology (Dr. Diop), Cheikh A. Diop University. Supported in part by NIH grant 1P5ODC03093 from the National Institute on Deafness and Other Communication Disorders, the International Hearing Foundation, and the Fullbright Scholarship Program. Reprint requests: Patricia Schachern, Room 226, Lions Research Building, 2001 6th Street SE, Department of Otolaryngology, University of Minnesota, Minneapolis,MN 55455. OtolaryngolHead Neck Surg 1998;118:283-5. Copyright 9 1998 by the AmericanAcademy of OtolaryngologyHead and Neck SurgeryFoundation, Inc. 0194-5998/98/$5.00 + 0 23/10/84735
genesis of otologic findings in AIDS can be provided by histopathologic studies of the temporal bone, there have been only five such reports to date. 9-13 The first study of a temporal bone from a patient with AIDS was reported by Kwartler et al. 9 in 1990. The patient had died from Cryptococcus neoformans meningitis after having been admitted for sudden hearing loss. Histopathologic study revealed necrosis of the cochlear and vestibular nerves. Necrosis had extended into the utricle and saccule and into the ampullae of the semicircular canal. The lesions were almost identical in the two ears, but neither temporal bone showed abnormality in the middle and external ears. In 1992 Chandrasekhar et al. l~ reported findings in 10 temporal bones from 5 patients seropositive for AIDS, only 1 of whom had an otologic history. Findings in these patients included petromastoiditis, perilymphatic precipitate, endolymphatic precipitate, neuroepithelial changes, and inflammatory changes in the middle ear. Pappas et al., u in two ultrastructural studies of the temporal bones of patients with H1V infections, described viral-like particles with morphologic characteristics of HIV in the cochlea and the vestibular end organs. 12 The largest histopathologic study, by Michaels et al., 13 described findings in 49 temporal bones from 25 patients: 5 with severe otitis media, 15 with low-grade otitis media, 2 with labyrinthine cryptococcosis, 1 with Kaposi's sarcoma deposit in the eighth nerve, and 6 with cytomegalovirus inclusions in cells of the middle and inner ears. We present a case study of a patient with AIDS whose temporal bones revealed massive fungal infection. METHOOS
Temporal bones were removed at autopsy, fixed in 10% buffered formalin, decalcified in trichloroacetic acid, and embedded in celloidin. Sections were cut at thicknesses of 20 gm each, stained with hematoxylin and eosin, and examined with light microscopy. Findings from the patients' clinical charts were examined and summarized for correlation. 283
284 DIOP et al.
Fig. I. Middle ear cavity and a portion of the external canal are filled with purulent effusion (P), granulation tissue (G), and colonies of A. fumigatus (A). There is ossicular erosion (arrows) of the incus (I) and the head of the stapes (S). (Hematoxylin and eosin stain; original magnification x18.)
Fig. 2, Purulent effusion (P) and granulation tissue (G) fill the middle ear and mastoid. There are scaffered areas of necrosis (arrows) and colonies of Aspergillus (A). F, Facial nerve; LC, lateral canal; PC, posterior canal. (Hematoxylin and eosin stain; original magnification x14.)
RESULTS
Clinical History A 21-year-old woman was first seen for bulimia in 1987 at the outpatient psychiatric clinic of the University of Minnesota. Because of intravenous drug use, a blood infection, and hepatitis, the previous year (1986), she had been tested for HIV and found to be seropositive. Her first otolaryngologic evaluation was in 1991, for nasal obstruction, rhinorrhea, and posterior drainage; the ears appeared normal, but the nasal
Otolaryn~ologyHead and NeckSurgery February 1998
Fig. 3. High magnification of Aspergillus in the middle cranial fossa. (Hematoxylin and eosin stain; original magnification x 125.)
mucosa appeared edematous. She returned to the otolaryngology clinic in 1992 for pain in the left ear, and antibiotics were prescribed for what was considered to be otitis media. A month later she returned to the otolaryngology department with diminished heating and pain in that ear. The left ear demonstrated extensive mastoiditis with drainage of yellow fluid; there was effusion in the right ear, and she had a cytomegalovirus retinitis. Cultures from the left ear revealed Aspergillus fumigatus, and amphotericin, vancomycin, and metronidazole (Flagyl) were prescribed. Five months later she returned, still reporting acute left otalgia and was observed to have a bulging posteroinferior wall. There was painful and fluctuate swelling behind the auricle, which was diagnosed as Bezold's abscess. CT scan and MRI of the brain showed extensive osteomyelitis and cerebral abscess. Discussion among the patient, her family, and teams from the Infectious Diseases, Neurosurgery, and ENT Departments concluded that debridement of this massive infection would not be in the patient's best interest because of the immediate morbidity associated with the procedure, the difficulty of dural closure, and the poor likelihood that this infection would be cured even with aggressive therapy. A Hickman catheter was placed for simple drainage, and a culture revealed A. fumigatus, for which broad-spectrum antibiotics were added to the continued amphotericin. Four months later the patient died at 27 years of age. She had been taking the following medications: AZT, Bactrim, dideoxycytidine, acyclovir, griseofulvin, vancomycin, and amphotericin B. Autopsy the same day revealed an extensive mastoid abscess on the left with intracranial extension; abscess of the left cerebellar hemisphere
OtolaryngologyHead and Neck Surgery
DIOP et al. 285
Volume 118 Number 2
and temporal lobe that cultured multiple organisms of
Aspergillus; d i s s e m i n a t e d a t y p i c a l m y c o b a c t e r i a l infection (Mycobacterium avium) i n v o l v i n g the mesenterium, the periaortic, and peripancreatic lymph nodes, the spleen, the liver, and the left mastoid region; acute hemorrhagic necrotizing bronchopneumonia; and nodular hyperplasia of the liver.
Temporal Bone Findings General rarefaction o f the bone marrow was observed. In the right ear, there was moderate serous effusion in the tympanic cavity, and occasional inflammatory cells were seen in the hypotympanum. In the left ear the cochlea showed slight serous labyrinthitis, and in the tympanic cavity there was abundant effusion with polymorphonuclear cells and granulation tissue. All ossicles in the left eat" showed massive destruction, except the stapedial footplate and the end of the short process of the incus. The horizontal segment of the left bony facial canal was eroded. There was extensive osteomyelitis of the left mastoid, which was filled with granulation tissue, purulent effusion, and necrosis. M a n y colonies having septated hyphae typical of Aspergillus were noted in mastoid cells, tympanic cavity, eustachian tube, and external ear canal (Figs. 1, 2, and 3); a wide perforation of the tympanic membrane drained purulent effusion into the external ear. Colonies of AspergiUus surrounded by purulent effusion were also found in the posterior cranial fossa.
DISCUSSION For seropositive patients, otologic symptoms can be illuminated with several diagnostic tests: audiologic studies can reveal sensorineural or conductive hearing losses; and CT and MRI are useful in identifying lesions of the middle and inner ear. Biopsies are recommended to rule out carcinoma or other tumors of the external or middle ear. Cytology study of drainage can identify mycotic, protozoal, or mycobacterial infections of the ear. Our patient fit the CDC criteria for diagnosis of AIDS: she was seropositive, within a high-risk group, and had opportunistic infections, including Aspergillus. Exposure to AspergiUus and other fungi is quite natural, but although it is n o r m a l l y u n c o m m o n for Aspergillus to become pathogenic, this situation is becoming more and more frequent in immune systems compromised by AIDS or other conditions or agents
such as leukemia, long-term steroid therapy, cytotoxic chemotherapy, diabetes mellitus, b r o a d - s p e c t r u m antibiotic use, and the like. In a large study by Michaels et al., 13 two patients had cryptococcal infections in the labyrinth, but our patient showed no fungal infiltration in the inner ear. However, it was remarkable that her abscess extended from the mastoid into the posterior cranial fossa. The question of the route followed by fungal mastoiditis is difficult to answer: Does it follow the nasopharynx, go through the external ear by erosion, or is it blood-borne? A n d as a result there is a dilemma over whether to use aggressive treatment or the "conservative" treatment used in this case. We thank Noriko Morizono for the temporal bone processing and Sherry Fulton for the photography.
REFERENCES 1. Center for Disease Control and Prevention. Statistics from the Center for Disease Control and Prevention.AIDS 1995;9:103-5. 2. Marcusen D, Sooy CD. Otolaryngologic and head and neck manifestations of acquired immunodeficiency syndrome (AIDS). Laryngoscope 1985;95:401-5. 3. Kohan D, Rothstein SG, Cohen NL. Otologic disease in patients with acquired immunodeficiency syndrome. Ann Otol Rhinol Laryngol 1988;97:636-40. 4. Gherman CR, Ward RR, Bassis ML. Pneumocystiscarinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiencysyndrome. Am J Med 1988;85:250-2. 5. Breda SD, Hammerschlag PE, Gigliotti F, Schinella R. Pneumocystis carinii in the temporal bone as a primary manifestation of the acquired imrnunodeficiencysyndrome.Ann Otol Rhinol Laryngol 1988:427-31. 6. Strauss M, Fine E. Aspergillus otomastoiditis in acquired immunodeficiency syndrome. Am J Otol 1991;12:149-53. 7. Park S, Wunderlich I-I, Goldenberg RA, Marshall M. Pneumocystiscarinii in the middle ear. Arch Otolaryngol Head Neck Surg 1992;118:269-70. 8. Lalwany AK, Sooy CD. Otologic and neurologic manifestations of the acquired immunodeficiency syndrome. Otolaryngol Clin North Am 1992;25:!183-97. 9. Kwartler JA, Linthicum FH, Jahn AF, Hawke M. Sudden hearing loss due to AIDS-related cryptococcal meningitis--a temporal bone study. Otolaryngol Head Neck Surg 1990;104:265-9. 10. Chandrasekhar S, Silverls V, Chandrasekhar HK. Flistopathologic and ultrastructural changes in the temporal bones of HIV infected human adults. Am J Otol 1992;13:207-14. 11. Pappas DG, Chandrasekhar HK, Lim DJ, Hillman DE. Ultrastructural findings in the cochlea in AIDS cases. Am J Oto| 1994;15:456-65. 12. Pappas DG. Roland JT, Lira J, Lai A, I-Iillman DE. Ultrastructural findings in the vestibular end-organs of AIDS cases. Am J Otol 1995;16:140-5. 13. Michaels L, Soucek S, Liang J. The ear in the acquired irnmunodeficiency syndrome: I. Temporal bone histopathologic study. Am J Otol 1994;15:515-22.
S i n c e the first report of AIDS in 1980, the medical community and the whole of society have been challenged by the various aspects of this disease. Statistics from the Center for Disease Control and Prevention (CDC) in Atlanta, Georgia, showed 401,749 cases of AIDS in the United States as of June 1994, comprising all age groups and a wide variety of clinical aspects. 1 Because of the polysystemic nature of this illness, patients can have clinical features that shape-shift in relation to opportunistic infections, tumors, viruses, and side effects from the various drugs used to relieve their conditions. Clinical aspects of this syndrome also vary according to the current status of each particular patient's immune system. Therefore the myriad of challenges brought forth by this disease encompass the entire medical community. Either for primary care or when referred for evaluation, 40% of patients with AIDS will consult an otolaryngologist, who must deal with opportunistic infections, side effects of several drugs, tumors, or other viral infections. 2 These patients' common otologic symptoms include vertigo, otalgia, otorrhea, and hearing loss. Many investigators have reported otologic manifestations in patients with AIDS, but most such studies have been clinical. 2-8 Although insight into the patho-
From the University of Minnesota Otitis Media Research Center, Department of Otolaryngology(Drs. Diop and Paparella and Ms. Schachern), University of Minnesota Medical School; The Minnesota Ear, Head and Neck Clinic (Dr. Paparella); and the Department of Otolaryngology (Dr. Diop), Cheikh A. Diop University. Supported in part by NIH grant 1P5ODC03093 from the National Institute on Deafness and Other Communication Disorders, the International Hearing Foundation, and the Fullbright Scholarship Program. Reprint requests: Patricia Schachern, Room 226, Lions Research Building, 2001 6th Street SE, Department of Otolaryngology, University of Minnesota, Minneapolis,MN 55455. OtolaryngolHead Neck Surg 1998;118:283-5. Copyright 9 1998 by the AmericanAcademy of OtolaryngologyHead and Neck SurgeryFoundation, Inc. 0194-5998/98/$5.00 + 0 23/10/84735
genesis of otologic findings in AIDS can be provided by histopathologic studies of the temporal bone, there have been only five such reports to date. 9-13 The first study of a temporal bone from a patient with AIDS was reported by Kwartler et al. 9 in 1990. The patient had died from Cryptococcus neoformans meningitis after having been admitted for sudden hearing loss. Histopathologic study revealed necrosis of the cochlear and vestibular nerves. Necrosis had extended into the utricle and saccule and into the ampullae of the semicircular canal. The lesions were almost identical in the two ears, but neither temporal bone showed abnormality in the middle and external ears. In 1992 Chandrasekhar et al. l~ reported findings in 10 temporal bones from 5 patients seropositive for AIDS, only 1 of whom had an otologic history. Findings in these patients included petromastoiditis, perilymphatic precipitate, endolymphatic precipitate, neuroepithelial changes, and inflammatory changes in the middle ear. Pappas et al., u in two ultrastructural studies of the temporal bones of patients with H1V infections, described viral-like particles with morphologic characteristics of HIV in the cochlea and the vestibular end organs. 12 The largest histopathologic study, by Michaels et al., 13 described findings in 49 temporal bones from 25 patients: 5 with severe otitis media, 15 with low-grade otitis media, 2 with labyrinthine cryptococcosis, 1 with Kaposi's sarcoma deposit in the eighth nerve, and 6 with cytomegalovirus inclusions in cells of the middle and inner ears. We present a case study of a patient with AIDS whose temporal bones revealed massive fungal infection. METHOOS
Temporal bones were removed at autopsy, fixed in 10% buffered formalin, decalcified in trichloroacetic acid, and embedded in celloidin. Sections were cut at thicknesses of 20 gm each, stained with hematoxylin and eosin, and examined with light microscopy. Findings from the patients' clinical charts were examined and summarized for correlation. 283
284 DIOP et al.
Fig. I. Middle ear cavity and a portion of the external canal are filled with purulent effusion (P), granulation tissue (G), and colonies of A. fumigatus (A). There is ossicular erosion (arrows) of the incus (I) and the head of the stapes (S). (Hematoxylin and eosin stain; original magnification x18.)
Fig. 2, Purulent effusion (P) and granulation tissue (G) fill the middle ear and mastoid. There are scaffered areas of necrosis (arrows) and colonies of Aspergillus (A). F, Facial nerve; LC, lateral canal; PC, posterior canal. (Hematoxylin and eosin stain; original magnification x14.)
RESULTS
Clinical History A 21-year-old woman was first seen for bulimia in 1987 at the outpatient psychiatric clinic of the University of Minnesota. Because of intravenous drug use, a blood infection, and hepatitis, the previous year (1986), she had been tested for HIV and found to be seropositive. Her first otolaryngologic evaluation was in 1991, for nasal obstruction, rhinorrhea, and posterior drainage; the ears appeared normal, but the nasal
Otolaryn~ologyHead and NeckSurgery February 1998
Fig. 3. High magnification of Aspergillus in the middle cranial fossa. (Hematoxylin and eosin stain; original magnification x 125.)
mucosa appeared edematous. She returned to the otolaryngology clinic in 1992 for pain in the left ear, and antibiotics were prescribed for what was considered to be otitis media. A month later she returned to the otolaryngology department with diminished heating and pain in that ear. The left ear demonstrated extensive mastoiditis with drainage of yellow fluid; there was effusion in the right ear, and she had a cytomegalovirus retinitis. Cultures from the left ear revealed Aspergillus fumigatus, and amphotericin, vancomycin, and metronidazole (Flagyl) were prescribed. Five months later she returned, still reporting acute left otalgia and was observed to have a bulging posteroinferior wall. There was painful and fluctuate swelling behind the auricle, which was diagnosed as Bezold's abscess. CT scan and MRI of the brain showed extensive osteomyelitis and cerebral abscess. Discussion among the patient, her family, and teams from the Infectious Diseases, Neurosurgery, and ENT Departments concluded that debridement of this massive infection would not be in the patient's best interest because of the immediate morbidity associated with the procedure, the difficulty of dural closure, and the poor likelihood that this infection would be cured even with aggressive therapy. A Hickman catheter was placed for simple drainage, and a culture revealed A. fumigatus, for which broad-spectrum antibiotics were added to the continued amphotericin. Four months later the patient died at 27 years of age. She had been taking the following medications: AZT, Bactrim, dideoxycytidine, acyclovir, griseofulvin, vancomycin, and amphotericin B. Autopsy the same day revealed an extensive mastoid abscess on the left with intracranial extension; abscess of the left cerebellar hemisphere
OtolaryngologyHead and Neck Surgery
DIOP et al. 285
Volume 118 Number 2
and temporal lobe that cultured multiple organisms of
Aspergillus; d i s s e m i n a t e d a t y p i c a l m y c o b a c t e r i a l infection (Mycobacterium avium) i n v o l v i n g the mesenterium, the periaortic, and peripancreatic lymph nodes, the spleen, the liver, and the left mastoid region; acute hemorrhagic necrotizing bronchopneumonia; and nodular hyperplasia of the liver.
Temporal Bone Findings General rarefaction o f the bone marrow was observed. In the right ear, there was moderate serous effusion in the tympanic cavity, and occasional inflammatory cells were seen in the hypotympanum. In the left ear the cochlea showed slight serous labyrinthitis, and in the tympanic cavity there was abundant effusion with polymorphonuclear cells and granulation tissue. All ossicles in the left eat" showed massive destruction, except the stapedial footplate and the end of the short process of the incus. The horizontal segment of the left bony facial canal was eroded. There was extensive osteomyelitis of the left mastoid, which was filled with granulation tissue, purulent effusion, and necrosis. M a n y colonies having septated hyphae typical of Aspergillus were noted in mastoid cells, tympanic cavity, eustachian tube, and external ear canal (Figs. 1, 2, and 3); a wide perforation of the tympanic membrane drained purulent effusion into the external ear. Colonies of AspergiUus surrounded by purulent effusion were also found in the posterior cranial fossa.
DISCUSSION For seropositive patients, otologic symptoms can be illuminated with several diagnostic tests: audiologic studies can reveal sensorineural or conductive hearing losses; and CT and MRI are useful in identifying lesions of the middle and inner ear. Biopsies are recommended to rule out carcinoma or other tumors of the external or middle ear. Cytology study of drainage can identify mycotic, protozoal, or mycobacterial infections of the ear. Our patient fit the CDC criteria for diagnosis of AIDS: she was seropositive, within a high-risk group, and had opportunistic infections, including Aspergillus. Exposure to AspergiUus and other fungi is quite natural, but although it is n o r m a l l y u n c o m m o n for Aspergillus to become pathogenic, this situation is becoming more and more frequent in immune systems compromised by AIDS or other conditions or agents
such as leukemia, long-term steroid therapy, cytotoxic chemotherapy, diabetes mellitus, b r o a d - s p e c t r u m antibiotic use, and the like. In a large study by Michaels et al., 13 two patients had cryptococcal infections in the labyrinth, but our patient showed no fungal infiltration in the inner ear. However, it was remarkable that her abscess extended from the mastoid into the posterior cranial fossa. The question of the route followed by fungal mastoiditis is difficult to answer: Does it follow the nasopharynx, go through the external ear by erosion, or is it blood-borne? A n d as a result there is a dilemma over whether to use aggressive treatment or the "conservative" treatment used in this case. We thank Noriko Morizono for the temporal bone processing and Sherry Fulton for the photography.
REFERENCES 1. Center for Disease Control and Prevention. Statistics from the Center for Disease Control and Prevention.AIDS 1995;9:103-5. 2. Marcusen D, Sooy CD. Otolaryngologic and head and neck manifestations of acquired immunodeficiency syndrome (AIDS). Laryngoscope 1985;95:401-5. 3. Kohan D, Rothstein SG, Cohen NL. Otologic disease in patients with acquired immunodeficiency syndrome. Ann Otol Rhinol Laryngol 1988;97:636-40. 4. Gherman CR, Ward RR, Bassis ML. Pneumocystiscarinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiencysyndrome. Am J Med 1988;85:250-2. 5. Breda SD, Hammerschlag PE, Gigliotti F, Schinella R. Pneumocystis carinii in the temporal bone as a primary manifestation of the acquired imrnunodeficiencysyndrome.Ann Otol Rhinol Laryngol 1988:427-31. 6. Strauss M, Fine E. Aspergillus otomastoiditis in acquired immunodeficiency syndrome. Am J Otol 1991;12:149-53. 7. Park S, Wunderlich I-I, Goldenberg RA, Marshall M. Pneumocystiscarinii in the middle ear. Arch Otolaryngol Head Neck Surg 1992;118:269-70. 8. Lalwany AK, Sooy CD. Otologic and neurologic manifestations of the acquired immunodeficiency syndrome. Otolaryngol Clin North Am 1992;25:!183-97. 9. Kwartler JA, Linthicum FH, Jahn AF, Hawke M. Sudden hearing loss due to AIDS-related cryptococcal meningitis--a temporal bone study. Otolaryngol Head Neck Surg 1990;104:265-9. 10. Chandrasekhar S, Silverls V, Chandrasekhar HK. Flistopathologic and ultrastructural changes in the temporal bones of HIV infected human adults. Am J Otol 1992;13:207-14. 11. Pappas DG, Chandrasekhar HK, Lim DJ, Hillman DE. Ultrastructural findings in the cochlea in AIDS cases. Am J Oto| 1994;15:456-65. 12. Pappas DG. Roland JT, Lira J, Lai A, I-Iillman DE. Ultrastructural findings in the vestibular end-organs of AIDS cases. Am J Otol 1995;16:140-5. 13. Michaels L, Soucek S, Liang J. The ear in the acquired irnmunodeficiency syndrome: I. Temporal bone histopathologic study. Am J Otol 1994;15:515-22.