PAUL A. LEVINE, MD Case Report Edltor

Cytomegalovirus nfect on of the larynx in the acquired immunodefic ency syndrome RUSSELL A. MARELLI, MD, PAUL W. BIDDINGER, MD, and JACK L. GLUCKMAN, MD, Cincinnati, Ohio

C

ytomegalovirus (CMV), along with herpes simplex, varicella, and Epstein-Barr virus, is a member of the

odynophagia, nonproductive cough, hoarseness, nightsweats, and fever. Over the preceding 2 days, he had experienced increasing confusion and somnolence. herpes virus family. Like other herpesviruses, C M V The patient had previously been enrolled in an AIDS study can cause primary, latent and chronic persistent infecprotocol and reportedly had a surveillance blood culture postion.'.* After initial infection, the virus is shed in saliva, itive for CMV 16 months before admission. He was asympurine, semen, and cervical secretion^.^ Epidemiologic tomatic until 7 months before this admission when herpes studies suggest that the virus is sexually t r a n ~ m i t t e d . ~ , ~ simplex pharyngitis developed, which was treated with acyMore than half of a11 adults in industrialized nations clovir. He had remained on a treatment of clotrimazole troches have serologic evidence of previous infection.6 C M V is and zidovudine (AZT), in addition to acyclovir. even more widespread in developing countries' and On initial examination, the patient was noted to be hoarse, among homosexual males ,3,5.8 in whom seroprevalence mildly dyspneic, and disoriented. His temperature was 101" F. The general physical examination was normal. is nearly 100%. Laboratory tests revealed WBC count of 15001mm3with Primary C M V infection in the immunocompetent 57% segs, 19% bands, 15% lymphs, 4% monos, and 5% eos, adult is usually asymptomatic or produces a mild monoand a macrocytic anemia was identified with a hemoglobin nucleosis-like illness. Serious CMV-related disease is of 9.2 gldl. Serum chemistry was normal, except for an almost entirely limited to congenitally infected infants elevated SGOT. Urinalysis was normal. Room air arterial and patients with impaired cell-mediated immunity. blood gases were normal. Severe CMV-related disease is well-described in iatroX-ray films of the chest and sinuses were normal. CT scan genically induced (e.g., transplant patient^)'.^.'" and acof the head revealed a venous angioma of the right cerebellar quired immunodeficiency (AIDS). C M V is the most hemisphere, minimal cortical atrophy, and right maxillary and common cause of serious opportunistic viral infection sphenoid sinus mucosal thickening. in AIDS patients." Lumbar puncture revealed an elevated CSF protein (60 mg/dl), but normal glucose, gram stain, and cell count. CSF This article presents a case of C M V infection afVDRL, cryptococcal antigen, and cultures (bacterial, AFB, fecting the mucosa of the larynx, which to the best of and fungal) ultimately were negative. our knowledge represents the first such case reported. On flexible bronchoscopy performed by the pulmonary Because of the potential for airway compromise, C M V medicine service, a lesion of the right false vocal cord was laryngeal infection may have ominous implications for identified. Bronchial lavage revealed an acellular gram stain; the patient and otolaryngologist. rapid CMV assay (immunofluorescence) was positive; cytology was positive for CMV changes and negative for maligCASE REPORT nancy, fungal, and pneumocystis elements; silver stain was A 40-year-old HIV-positive homosexual man was seen in negative for pneumocystis. CMV immunofluorescence of the emergency room with a 2 week history of progressive blood was positive. The otolaryngology service was consulted and flexible fiFrom the Departments of Otolaryngology-Head and Neck Surgery beroptic laryngoscopy confirmed a yellowish white ulceration (Drs. Marelli and Gluckrnan) and Pathology and Laboratory Medof the right false vocal cord, with surrounding erythema and icine (Dr. Biddinger), University of Cincinnati Medical Center. edema. The right true vocal cord was normal except for dePresented at the 1991 Middle Section Triological Meeting, Milwaucreased motion. The airway was narrowed, but adequate. The kee, Wis., Jan. 27, 1991. remainder of the head and neck examination was normal. Received for publication April 9, 1991; accepted Aug. 19, 1991. The patient was started on a regimen of 1 gram cefotaxime Reprint requests: Jack L. Gluckman, MD, Department of Otolarintravenously every 6 hours, 3 15 mg acyclovir intravenously yngology-Head and Neck Surgery, University of Cincinnati Medevery 8 hours, and 40 mg hydrocortisone intravenously every ical Center, 231 Bethesda Ave., Cincinnati, OH 45267-0528. 23 14133526 6 hours. Since a candida infection was considered, the patient

'

~

296

Volume 106 Number 3 March 1992

CaseReports 297

Fig. I . Inflamed granulation tissue from the base of a laryngeal ulcer.

was started on 100 mg fluconazole by mouth daily and nystatin swish and swallow. Over the first few days of hospitalization, the patient became afebrile and his confusion diminished. His hoarseness and throat pain, however, failed to improve, and daily fiberoptic visualization of the larynx failed to demonstrate any resolution of the lesion. On the eighth day, direct laryngoscopy while the patient was under general anesthesia was performed, and the ulcerative lesion of the right false vocal cord was noted to extend into the ventricle, but not onto the true vocal cord. The left side of the larynx was normal. Cells for cytologic evaluation and multiple biopsies were taken for permanent histology and cultures (bacterial, AFB, fungal, viral). Gram stain revealed many WBCs and gram-positive cocci in clusters. KOH and PAS stains were negative for fungi. Cytopathology reported benign squamous epithelial cells and glandular epithelium. Malignant cells, fungal forms, and viral changes were not identified. Bacterial cultures ultimately grew coagulase-negative staphylococcus (staph epidermidis). Histopathology of the laryngeal biopsy revealed fragments of necrotic debris, inflamed granulation tissue, and rare cells with enlarged nuclei and intranuclear inclusions consistent with cytomegalovirus infection (Figs. 1 and 2). There was no evidence of neoplasm or fungal infection. The tissue sent for culture ultimately was positive for CMV. During hospitalization, CMV retinitis developed and the patient was immediately started on 5 mg ganciclovir/kg intravenously every 12 hours. Acyclovir, fluconazole, AZT, and antibiotics were discontinued. By day 12 of ganciclovir, there was a significant improvement noted in the patient's retinitis,

but the laryngeal mucosal lesion and cord paralysis remained unchanged. The patient remained in the hospital for 21 days and then was discharged with the ganciclovir administered by means of an indwelling central venous. A maintenance dose of 6 mg ganciclovirlkg daily, 5 times a week, was administered at home. The patient was seen in followup 1 month after discharge, with dramatic resolution of his laryngeal symptoms. Fiberoptic laryngoscopy revealed complete resolution of erythema and edema, with only a tiny residual ulcer of the right false cord, but persistent cord paralysis. After the patient had received ganciclovir for 6 months, the laryngeal examination was entirely normal except for right vocal cord paralysis. After 4 months of therapy, anemia developed in the patient; this necessitated a blood transfusion and discontinuation of AZT. Blood counts have subsequently stabilized; however, atypical mycobacteria (m. avium intracellulare) have been cultured from his blood. Other significant sequelae include a significant short-term memory loss, presumably fmm HIV encephalopathy, and blindness.

DISCUSSION C M V is commonly identified in asymptomatic HIVpositive, AIDS-related complex (ARC), and patients with AIDS. Nearly 100%of HIV-positive homosexual males are CMV seropositive.' Evidence for C M V infection is identified in 90% of AIDS cases at autopsy, and 50% of patients with AIDS have CMV viremia.4I-'' Because it was so frequently isolated from

OtolaryngologyHead and Neck Surgery

298 Case Reports

Fig. 2. Cell with intranuclear inclusion characteristic of cytomegalovirus.

AIDS patients early in the epidemic, CMV was regarded as a potential etiologic factor for AIDS. CMV itself is known to have some immunosuppressive effect' and has been epidemiologically associated with Kaposi's s a ~ c om a. '~ In autopsy series, CMV has been found in virtually every organ system. I 4 . l 6 Clinically significant CMV-related disease in the immunocompromised patient has predominantly been limited to the lung, gastrointestinal system, adrenal gland, retina, and central nervous system. While CMV is frequently associated with pneumocystic carinii in AIDS-related lung disease, CMV by itself is probably more significant in non-AIDS pneumonitis. l7 An AIDS-related Addison's disease may result from CMV adrenalitis." CMV encephalitis is often seen at but its actual incidence and clinical significance in AIDS is difficult to determine because of confusion with a similar encephalopathy caused by HIV.2 CMV is the only opportunistic infection to commonly involve the eye.2 Retinitis is the most common manifestation of CMV infection in patients with AIDS and tends to occur earlier than other CMV diseases.'8 Fundoscopic examination characteristically demonstrates areas of pallor and hemorrhage that produce visual field defects. The gastrointestinal tract is the second most common area for CMV disease in AIDS.'' Infection in the oral

cavity2' has been reported, but the esophagus, stomach, and colon are most commonly affected. Colitis, manifested by diarrhea and abdominal pain, frequently involves co-pathogens.'.I8 Gastritis and esophagitis manifest as epigastric or substernal pain and dysphagia. Esophageal lesions have ranged from small mucosal erosions with surrounding erythema and edema to large ulcers. ' ' . I 8 In a large series of AIDS patients,2' the overall incidence of serious CMV disease was 7.4% (5.7% retinitis and 2.2% gastrointestinal disease; a few patients had involvement of both areas). Because the virus is nearly ubiquitous, it is apparent that it is not pathogenic in every patient. Development of disease depends on the individual immune system interaction with the virus. For example, CMV pneumonitis in bone marrow transplant patients is almost uniformly fatal," whereas in patients with AIDS, it is much less agg~essive.'~.'~ It has been suggested that the tissue destruction in severe CMV pneumonitis is largely a result of the immune reaction to the virus rather than its direct cytopathologic effect.".** Patients with AIDS may not be able to mount a strong enough immune response to cause significant tissue damage. Alternatively, it may be that pneumonitis caused by primary CMV infection is naturally more severe than that resulting from reactivation. As mentioned earlier, seroprevalance of CMV is nearly 100% in HIV-infected individuals, and reac-

Volume 106 Number 3 March 1992

tivation of infection is probably the rule. In either case, it is apparent that the mere identification of the virus in the area does not by itself signify pathogenicity. In fact, the presence of CMV in bronchial washings is correlated with histologic evidence of pneumonitis only in patients with non-AIDS-related immunodeficiency.1i.’7 Because of the frequent identification of the virus without an apparent tissue response, most investigators require direct evidence of pathogenicity for a diagnosis of CMV-related disease.’ This may include the presence of an inflammatory reaction and typical viral inclusion bodies on histologic examination of infected tissue.2 Immunofluorescent stains may help to identify the virus in a histologic section, but are not sufficiently sensitive to rule out the d i a g n ~ s i s Because .~ the virus is shed in nearly all bodily secretions, a positive culture from a biopsy of the infected tissue is much more sufficient than a lavage or swab culture.’ In the case presented in this report, a tissue biopsy of the laryngeal lesion revealed an inflammatory reaction with CMV inclusion bodies, and was negative for evidence of other infectious disease or neoplasm. In addition, culture of biopsy tissue was positive for CMV and negative for other viruses and fungi. This suggests that CMV was not just a passive “inhabitant” in the larynx, but was, in fact, the cause of the disease. While CMV mucosal disease of the larynx has not been previously reported, inclusion bodies have been identified in the laryngeal nerves of a patient with vocal cord paralysis.23 In the same report, a second case of vocal cord paralysis was assumed to be caused by CMV because the patient was known to have disseminated CMV, and no other etiology was likely. However, histologic evidence of CMV infection was not obtained. In both cases of cord paralysis, no structural abnormality of the cord was identified. CMV inclusion bodies have also been seen at autopsy in the larynx of a patient with disseminated Kaposi’s sarcoma.24In this case, the inclusion bodies were identified “without abnormal tissue structure” and were apparently not directly responsible for any disease. Differential Dlognosis

In patients with AIDS, hoarseness is most commonly caused by edema of the true vocal cords resulting from chronic cough, previous radiation, or lymphatic obstruction from Kaposi’s sarcoma.zs Infections of the vocal cords are rare in HIV-positive individuals.26 Infections caused by Candida or herpes simplex occasionally involve the larynx and hypopharynx, but are more common in the oral cavity and esophagus.” Acute epiglottis may occur, but is usually caused by the same

Case Reports 299

organisms as in the immunocompetent patient.26 The most common causes of odynophagia and dysphagia in HIV-infected patients are Candida, herpes simplex, and CMV infections of the upper gastrointestinal tract.27 Gastroesophageal reflux is uncommon in AIDS.27Kaposi’s sarcoma may manifest in the skin, mucous membranes, or lymphoid tissue, and has been described in the larynx.28These lesions generally have a typical red, blue, or purple appearance. Biopsies from the larynx generally are not performed because the lesions tend to bleed significantly and a large specimen is usually needed for diagnosi~.’~ Other malignancies of the larynx should be ruled out. Lymphoproliferative disorders are common in AIDS, but Kaposi’s sarcoma is the only solid tumor epidemiologically linked to HIV.30 Therapy

Ganciclovir is the most important drug currently used for the treatment of sight- and life-threatening CMV disease.2,“ Ganciclovir is a structural analog of acyclovir differing only by the addition of a terminal hydroxymethyl group. However, it is up to 50 times more potent than acyclovir against CMV.* Intracellularly, ganciclovir is converted to its triphosphate form, which is an inhibitor of CMV DNA polymerase.’ In this manner, it terminates DNA chain production and viral replication, but has no direct effect on nonreplicating virus.’ Just as with acyclovir and herpes simplex, ganciclovir has no effect on latent CMV infection and must be used as maintenance therapy to prevent reactivation.‘.18 Ganciclovir has not affected the 80% to 90% mortality from CMV pneumonitis in bone marrow transplant patient^.',^' Addition of immunoglobulins may be helpful in this p ~ p u l a t i o n . ~ ‘Most . ~ ~ of the experience with ganciclovir has been in treatment of gastrointestinal disease and retinitis in patients with and it is regarded as being effective in these conditions. Its actual effectiveness is unclear because ganciclovir has been used since early in the AIDS epidemic (1984) and its presumed effectiveness has prevented placebo-controlled trials from being conducted. Ganciclovir is usually given in two phases. An induction phase of 2.5 to 5.0 mgikg intravenously every 8 to 12 hours for 10 to 14 days“ is followed by a maintenance phase consisting of 5.0 mg/kg in a single daily dose given 5 days a ~ e e k . ~ ‘ Stabilization ,’~ or improvement in retinitis is seen in up to 80% of pat i e n t ~ . ~ .and ~ ~ resolution .~’ of gastrointestinal symptoms in 60% to 70% of patients during induction therapy. Recurrence is to be expected if maintenance therapy is not continued. In a prospective study of maintenance ganciclovir,” CMV retinitis remained stable longer (53.8 days) when therapy was not interrupted

OtolaryngologyHead and Neck Surgery

300 Case Reports

than when maintenance therapy was deferred (18.8 days). A major disadvantage to using ganciclovir is its poor oral bi~availability,~'which necessitates intravenous administration. Maintenance therapy, therefore, is inconvenient and requires use of long-term intravenous catheters. The major toxicity of ganciclovir is myelosuppression with up to 30% or more of patients requiring dosage adjustment for severe neutropenia and/ or transfusion for anemia.34-36 It is unfortunate that zidovudine (AZT) is also myelosuppressive and may be synergistic in this regard with ganciclovir.*,'* Foscarnet (phosphonoformate) is a potent inhibitor of herpes virus DNA polymerases,'." which have been used most extensively in Europe. Early reports suggest that the drug is effective for CMV-related disease in AIDS'," without significant myelotoxicity,2.'8but further study is needed. Because latent CMV infection and immune suppression are life-long in patients with AIDS, maintenance therapy must also be continued for life. This makes the infectious complications of long-term intravenous therapy and ganciclovir toxicity life-long risks. Certainly, patients without well-documented CMV-related disease should not be subjected to these risks. Nor should ganciclovir be withheld from those with serious CMV infections. It is for these reasons that accurate diagnosis of CMV-related disease is especially critical. The patient presented here underwent a 21 day induction phase of ganciclovir, followed by a few weeks of maintenance therapy before his laryngeal symptoms began to improve. At last followup, he had been on ganciclovir maintenance for 6 months with no recurrence of laryngeal mucosal disease, but with a persistent vocal cord paralysis. His blindness developed rather suddenly after about 5 months of stabilization of the CMV retinitis. Possibly the mycobacterium avium intracellulare bacteremia played a role in this. The only complication of therapy has been anemia, which required blood transfusion. This occurred after 4 months of ganciclovir with AZT. The AZT was discontinued and his blood cell counts have stabilized. SUMMARY

CMV is the most important viral opportunist in patients with AIDS. Nearly all patients with AIDS have been exposed to CMV and the virus can be isolated from many. When CMV-related disease occurs in AIDS, it has usually involved the eye or gastrointestinal tract. In lesions in which CMV is the suspected etiology, evidence of direct pathogenicity of the virus should be obtained, usually histologically. Accurate diagnosis is

essential because long-term therapy with a relatively toxic drug (ganciclovir) is indicated. We have presented a case of CMV infection of the larynx that responded, albeit slowly, to ganciclovir. Additional cases may arise as the prevalence of AIDS increases. Because of the potential for airway compromise and the tendency toward chronicity, CMV infection of the larynx should be of a significant concern both for the patient and the otolaryngologist.

REFERENCES

1. Jeffries DJ. The spectrum of cytomegalovirus infection and its management. J Antimicrob Chemother 1989;23(Suppl E):l-10. 2. Tyms AS, Taylor DL, Parkin JM. Cytomegalovirus and the acquired immunodeficiency syndrome. J Antimicrob Chemother 1989;23(S~pplA):89-105. 3. Mintz L, Drew WL, Miner RC, et al. Cytomegalovirus infections in homosexual men. An epidemiological study. Ann Intern Med 1983;99:326-9. 4. Handsfield HH, Chandler SH, Caine VA, et al. Cytomegalovirus in six partners: evidence for sexual transmission. J Infect Dis 1985;15I :344-8. 5. Drew WL, Mintz L, Miner RC, et al. Prevalence of cytomegalovirus infection in homosexual men. J Infect Dis 1981343: 188-92. 6 . Stern H, Elek SD. Incidence of infection with cytomegalovirus in normal population: serologic study in greater London. J Hyg (Camb.) 1965;63:79-87. 7. Griffiths PD. Diagnosis of cytomegalovirus infection. J Antimicrob Chemother 1989;23(Suppl E): 1 1-6. 8. Greenberg SB, Linder S , Baxter B, et al. Lymphocyte subsets and urinary excretion of cytomegalovirus among homosexual men attending a clinic for sexually transmitted diseases. J Infect Dis 1984;150:330-3. 9. Snydman DR, Werner BG, Heinze-Lacey B, et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. N Engl J Med 1987;317:104954. 10. Myers ID, Fleurnoy N, Thomas ED. Non-bacterial pneumonia after allogenic marrow transplantation: a review of ten years' experience. Rev Infect Dis 1982;4:1119-32. 11. Jacobson MA, Mills J . Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;108:585-94. 12. Quinnan GV, Masur H, Rook AH, et al. Herpesvirus infections in the acquired immune deficiency syndrome. JAMA 1984;252: 72-7. 13. Pass HI, Potter DA, Macher AM, et al. Thoracic manifestations of the acquired immune deficiency syndrome. J Thorac Cardiovasc Surg 1984;88:654-8. 14. Reichert CM, O'Leary TJ, Levens DL, et al. Autopsy pathology in the acquired immune deficiency syndrome. Am J Pathol 1983;112:357-82. 15. Giraldo G, Beth E, Henle W, et al. Antibody patterns to herpesviruses in Kaposi's sarcoma. 11. Serological association on American Kaposi's sarcoma with cytomegalovirus. Int J Cancer 1978;22:126-31. 16. Welch K, Finkbeiner W, Alpers CE, et al. Autopsy findings in the acquired immune deficiency syndrome. JAMA 1984;252: 1152-9.

Volume 106 Number 3

Case Reports 301

March 1992

17. Murray JF, Felton CP, Garay SM, et al. Pulmonary complications of the acquired immunodeficiency syndrome: report of a national heart, lung, and blood institute workshop. N Engl J Med 1984;310: 1682-8. 18. Pinching AJ. Cytomegalovirus infection in the acquired immune deficiency syndrome. J Antimicrob Chemother 1989;23(Suppl E):31-6. 19. Post MJ, Hensley GT, Moskowitz LB, et al. Cytomegalic inclusion virus encephalitis in patients with AIDS: CT, clinical and pathological correlation. Am J Roentgen01 1986;146:122934. 20. Brahim JS, Roberts MW. Oral manifestation of human immunodeficiency virus infection. Ear Nose Throat J 1990;69:464-74. 21. Jacobson MA, O’Donnell JJ, Porteous D, et al. Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immune deficiency syndrome: Prevalence, natural history, and response to ganciclovir therapy. Q J Med 1988;67:473-86. 22. Grundy JE, Shanley JD, Griffiths PD. Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition? Lancet 1987;2996-9. 23. Small PM, McPhaul LW, Sooy CD, et al. Cytomegalovirus infection of the laryngeal nerve presenting as hoarseness in patients with acquired immunodeficiency syndrome. Am J Med 1989;86:108-10. 24. Jensen OA, Gerstoft J , Klen Thomsen H, et al. Cytomegalovirus retinitis in the acquired immunodeficiency syndrome (AIDS): light-microscopical, ultrastructural, and immunohistochemical examination of a case. Acta Ophthalmol 1984;62:1-9. 25. Sooy CD. impact of AIDS on otolaryngology. In: Bluestone CD, Blackman DE, and Krause CJ, eds. Advances in otolaryngologic head and neck surgery, vol. 1. Chicago: Yearbook Medical Publishers, Inc., 1987:l-28. 26. Ogniebene FP. Upper and lower airway manifestations of human

27. 28. 29. 30.

31.

32.

33.

34.

35.

36.

immunodeficiency virus infection. Ear Nose Throat J 1990;69:424-3 1 , Raufman JP. Odynophagia/dysphagia in AIDS. Gastroenterol Clin North Am 1988;17:599-614. Levy FE, Tansek KM. AIDS-associated Kaposi’s sarcoma of the larynx. Ear Nose Throat J 1990;69:177-84. Ognibene FP, Shelhamer JH. Kaposi’s sarcoma. Clin Chest Med 1988;9:459-65. Wenig BM, Kuruvilla A, Goldrich MS, et al. Pathologic manifestations of acquired immunodeficiency syndrome in the head and neck. Ear Nose Throat J 1990;69:406-15. Shep DH, Dandliker PS, de Miranda P, et al. Activity of 9-12. hydroxy- I-(hydroxymethyl) ethoxymethyl] guanine in the treatment of cytomegalovirus pneumonia. Ann intern Med 1985;103:368-73. Bratanow N , Ash RC, Turner P, et al. The use of 9 (1,3-dihydroxy-2-propoxymethyl) guanine (ganciclovir, DHPG) and intravenous immunoglobulin (IVIG) in the treatment of serious cytomegalovirus (CMV) infections in thirty-one allogenic bone marrow transplant (BMT) patients. Blood 1987;7O(Suppl 1):302a. Winston DL, Pollard RB, Ho WG, et al. Cytomegalovirus immune plasma in bone marrow transplant recipients. Ann Intern Med 1982;97:11-8. Laskin OL, Cedarberg DM, Mills J , et al. Gancyclovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med 1987;83:201-7. Chachoua A, Dieterich D, Krasinski K, et al. 9 (1.3-dihydroxy2-propoxymethyl) guanine (ganciclovir) in the treatment of cytomegalovirus gastrointestinal disease with the acquired immunodeficiency syndrome. Ann Intern Med 1987;107:133-7. Jacobson MA, de Miranda P. Cedarberg DM, et al. Human pharmcokinetics and tolerance of oral ganciclovir. Antimicrob Agents Chemother 1987;3 I: 1251-4.