Current Eye Research
Volume 10 supplement 1991
External ocular herpesvirus infections in immunodeficiency
Jay S.Pepose
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Departments of Ophthalmology and Visual Sciences and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
ABSTRACT Infections of the eye with members of the herpes family of viruses (e.g. HSV, CMV, VZV) are frequent manifestations of acquired and inherited defects in cell mediated immunity. Herpesvirus infections in the immunocompromised may reflect frequent viral reactivation from the latent state, as well as extensive productive infection of ocular structures following reactivation or primary infection. A review of experimental and clinical studies of both acquired and inherited immune dysfunction implicates specific immune mechanisms influencing the establishment of latency, viral reactivation and the control of active viral replication in ocular tissues. INTRODUCTION The immune system may have a profound effect on the biology of herpetic infections at several stages (Figure 1): (1) the acute primary infection, (2) the initial spread of virus and the establishment of latency, (3) reactivation from latency, (4) control of active recurrent infection, ( 5 ) protection from exogenous reinfection with new viral strains. A review of common external ocular herpetic disease in clinical and experimental forms of acquired and inherited immunodeficiency points to specific immunologic mechanisms affecting each of these stages. HERPES SIMPLEX KERATITIS IN THE IMMUNOCOMPROMISED Primaw infection Primary herpes simplex virus (HSV) infection can cause extensive ocular and systemic morbidity in the immunocompromised, such as neonates and individuals with acquired or inherited defects in cellular immunity. It is well established that neonates have compromised cellular immune function. Most newborns with HSV infection have no detectable T-lymphocyte responses to HSV until 2-4 weeks after the onset of infection (1,2) This is thought to reflect a low responder cell frequency rather than impairment in monocyte processing. In addition, infected
newborns have decreased production of alpha interferon in response to HSV antigen compared to adults with primary HSV (l), as well as decreased production of gamma interferon after HSV stimulation (3). Whereas 80% of neonatal HSV infection is caused by HSV type 2, both HSV types 1 and 2 have been associated with neonatal keratitis. HSV-infected peripheral blood mononuclear cells appear to play a major role in disseminating the virus in a rabbit model of neonatal ocular herpes simplex infection (4). Deficiencies in cellular immunity and lymphokine generation described in the previous paragraph may influence both the nature of neonatal herpetic keratitis and the likelihood of viral dissemination. In a study of ophthalmic manifestations of neonatal HSV, Nahmias et a1 (5) reported a 7% incidence of keratitis (19/297 patients examined). A study of late ophthalmic signs of neonatal HSV (6) revealed a 6% incidence of keratitis in patients with disseminated disease, all with resulting vision of 20/40 or better. This relatively good long term vision following neonatal HSV keratitis could reflect a paucity of cells infiltrating neonatal corneal lesions, as a result of impaired cellular immunity. Much of the early corneal opacification in these patients may reflect reversible corneal edema, rather than stromal inflammation. This may be analogous to the observation that congenitally athymic (nude) mice, unlike their euthymic littermates, failed to develop stromal keratitis. Stromal disease could be restored by reconstitution with T-cells from HSV-immune animals (7). Natural killer (NK) cell function is also decreased in neonates. NK cells have been demonstrated to play a protective role against the development of fatal HSV infections in mice (8). A 13 year old girl with complete and specific lack of natural killer (NK) cells developed a variety of life threatening primary herpes virus infections,
Received on August 3 , 1990: acceptcd on October 2 5 , 1990
(a Oxford University Press
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Current Eye Research
Figure 1. The immune res onse may influence the biology of herpes simplex virus in ection at several discrete phases.
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emphasizing the critical protective role of NK cells in limiting disseminated infection (9). Transplacental transfer of antibodies to the neonate, while not totally protective, may serve to ameliorate HSV infection. For example, antibody-dependent cellular cytotoxicity antibody levels or high levels of neutralizing antibodies are independently associated with absence of HSV dissemination (10). Several investigators have demonstrated that passive transfer of antiherpes antibody will prevent HSV stromal keratitis in mice following primary corneal inoculation (11-13). Shimeld et a1 (14) and Tullo and co-workers (15) demonstrated that the effect of passive immunization does not limit the severity of corneal epithelial disease, but restricts viral spread within the nervous system with consequent transport back to the eye. The protective role of antibody could also explain the more widespread dissemination of HSV in mice with severe combined immunodeficiency (SCID), in which both T and B-cell function are severely diminished, compared to congenitally athymic mice (16). Several studies also suggest an active role for antibody to HSV in the establishment and maintenance of latency. Passive transfer of antiviral antibodies reduces the establishment of lytic and latent infection in non-ophthalmic portions of the trigeminal ganglia following corneal inoculation (14,15). In a modified murine model of HSV latency and reactivation, we have found that passive immune transfer tends to drive the virus directly into neuronal latency (16). In experiments transplanting latently
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infected ganglia in millipore filters to naive or immune mice, Stevens and Cook (17) further implicated a role for antiviral IgG in the maintenance of the latent state in neurons. Clinically, however, there appears to be no correlation between neutralizing antibodies and the incidence of recurrent disease (18). Following primary herpetic keratitis in inbred mice, a marked variation in the number of latently infected cells was noted between inbred strains (19). It has not, however, been determined which specific immune mechanisms contribute to or underlie this genetic difference in susceptibility to the establishment of latency. HSV reactivation Herpes simplex virus (HSV) reactivation appears to be more frequent and often, more serious, in patients with defects in cell mediated immunity (20) (e.g. organ transplant recipients, patients given cytotoxic agents for malignancy, malnourished individuals, burn patients, those with skin conditions such as eczema, or inherited cellular immune defects). However, most frequent signs of reactivation in these patients involve nasolabial disease. The specific incidence of herpetic keratitis or asymptomatic viral shedding in tears (21) of the immunocompromised has not been systematically studied. Various systemic immunosuppressive regimens have been shown to induce reactivation of latent HSV in rabbits (22,23) and mice (24-27), with recovery of virus in the tear film. When accompanied by ultraviolet irradiation, recurrent corneal lesions have been frequently noted in immunosuppressed rabbits (22) and mice (26). While topical corticosteroids may not alter the incidence of HSV reactivation in animals (B),they increase the duration of viral shedding once reactivation has occurred. With so many diverse stimuli capable of triggering HSV reactivation from the ganglia, the mechanisms underlying reactivation by immunosuppressive drugs may be complex. T-cells have been demonstrated in rabbit trigeminal ganglia following the acute infection (29) and mononuclear cells are prominent in the trigeminal ganglia of small proportion of NIH mice following reactivation (16). However, there has been no direct correlation shown between viral reactivation and local cellular infiltrates within the ganglia. Immunosuppressive drugs that induce HSV reactivation may not necessarily act via a conventional immunologic pathway alone. Recent studies have shown that during
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Current Eye Research herpetic latency, viral transcripts are made from the opposite strand of DNA coding for the immediate early gene, ICPO (30-32). Mutant strains of HSV lacking the genetic information coding for latency associated transcripts (LATs) reactivate with reduced efficiency (33,34), implicating an important role for LATs in facilitating reactivation. Other studies have shown that many drugs that modulate cyclic AMP levels may influence HSV reactivation in vivo (35). One factor that may link these two findings is the demonstration of a cyclic AMP responsive element within the promoter region of the LATs gene and the presence of a degenerate CAMPresponsive element in the ICPO promoter (36) -- two genes central to viral reactivation. As a precedent that immunosuppressive agents may affect viral transcription, dexamethasone has been shown to influence the expression of the latencyrelated gene of bovine herpesvirus 1(37). Another way in which immunosuppression may increase the frequency of recurrent HSV lesions, involves the hypothesis of Hill and Blyth (38). They proposed that infectious particles could be produced periodically in the ganglia during latency and transported to the corneal nerve endings via retrograde axoplasmic flow. It is possible that immunosuppression does not so much influence the frequency of HSV reactivation at the ganglionic level, but rather the immune response at the periphery causing exacerbations of an otherwise limited or totally asymptomatic infection. For example, following immunosuppression with cyclosporine A, rabbits developed more extensive lesions (39), and shed virus for a longer duration in a model of primary herpes keratitis (39,40). A review of the literature reveals numerous anecdotal reports of HSV keratitis amongst patients with acquired and inherited forms of cell mediated immunodeficiency. Several studies cite cases of keratoconjunctivitiswith chronic viral shedding, ulceration and/or perforation, frequently occurring within one month of renal (41-44) or bone marrow transplantation (49, or in association with graftversus-host disease (46). Herpetic recurrence correlated with the dose of immunosuppression and the time of greatest defects in lymphocyte transformation and interferon production in response to HSV antigens (47,48). Chronic and prolonged ulcerative and stromal HSV keratitis has been also associated with other forms of predominantly depressed cellular immunity indicating the Wiskott-Aldrich
syndrome (49), severe atopic eczema (44,50) or in association with measles, malaria and malnutrition in children (51). Corneal disease in these children is often bilateral and may be a prelude to viral dissemination and death. Similarly,bilateral recurrent HSV keratitis, which is far rarer than bilateral primary HSV keratitis, has been reported in an adult with alcoholic hepato-cirrhosis, chronic anemia and bronchitis (52), who was likely immunosuppressed. In contrast to disorders affecting predominantly cellular immunity, primary humoral immunodeficiencies (e.g. Xlinked aggamaglobulinemia,IgA deficiency) does not appear associated with an increased incidence of recurrent herpetic infection nor unusual pathology once reactivation has occurred (53). A single case report of recurrent herpes simplex stromal keratitis in congenital dysgammaglobulinemia showed a good, typical response to conventional antiviral therapy with low dose topical steroids, resulting in resolution with minimal scarring (54). Control of recurrent infection Once reactivation has occurred, herpes simplex keratitis may have atypical features in patients with cellular immunodeficiency. It is unclear whether AIDS patients overall have a higher incidence of HSV keratitis than in immunocompetent individuals. However, once reactivation has occurred in an individualwith AIDS, the course of HSV keratitis is generally prolonged and recurrences are frequent (55). Epithelial disease has an unusual predilection for peripheral cornea and limbus and average healing time with topical antiviral therapy is three weeks. One AIDS patient developed HSV epithelial keratitis refractory to antiviral therapy, which healed after three weeks of topical recombinant interferon-alpha 2a (56). Stromal disease in these patients is uncommon (55), probably reflecting their inability to mount an adequate cell mediated immune response. Similar features of HSV keratitis have been noted in other patients with deficient cellular immunity, such as transplant recipients (41,44). A reduced incidence of HSV stromal keratitis has been demonstrated in susceptible immunogenetic strains of mice after pretreatment with cyclophosphamide (27) and by other forms of depressed delayed type hypersensitivity (57,58). Whether a decrease in the number or function of migratory local immune cells, such as Langerhans cells, also plays a modulatory role in ocular lesion formation (59) in
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immunocompromisedpatients and experimental animals deserves further study. OCULAR VARICELLA-ZOSTER VIRAL INFECTIONS IN THE IMMUNOCOMPROMISED Primarv infections Whereas primary varicella generally runs a benign course in the immunocompetent, it can be a cause of grave morbidity and mortality in the immunocompromised. Ocular signs are generally confined to vesicular lesions of the conjunctiva, rare dendritic figures or disciform keratitis. Patients with deficient cell mediated immunity are at high risk (20-35%)for visceral dissemination to lung, liver or brain with a 7-30%mortality rate (60). High risk patients include children with acute leukemia, non-Hodgkin’s lymphoma, solid tumors, Hodgkin’s disease and after bone marrow transplantation (61). Dissemination was more common in patients with lymphocyte counts below 500/mm2 on the first day of infection (60) and the risk was diminished in patients when chemotherapy was halted during the varicella incubation period. As compared to immunocompetent children, children with cancer developed less antibody to certain varicellazoster glycoproteins, but not to others (62). In contrast, Tlymphocyte function plays a pivotal role in recovery from primary infection and in prevention of subsequent reactivation. Reduced lymphocyte proliferation to varicellazoster has been associated with chemotherapy for leukemia and may be of predictive value for patients at risk for reactivation. Monocyte mediated antigen presentation appears intact, while virus-specificlymphocyte numbers decline and may underlie the immunodeficiency to varicella in these children (63). Fatal attacks of varicella have also been reported in patients with primary combined immunodeficiencies including Nezeloff syndrome and cartilage-hair hypoplasia (64). Varicella-zoster immune globulin may ameliorate or prevent varicella in the immunocompromised, but has no effect on zoster infection or dissemination (65). Live, attenuated varicella vaccine (Oka Strain) protects high risk immunosuppressed individuals who have been exposed to varicella or zoster (66). However, immunity may quickly wane in these patients, and vaccine induced rashes are common. Zoster has been reported following vaccination, and can be due to either reactivation of the vaccine strain or to exogenous infection (67). 90
Varicella in children with HIV infection manifests differently than in pediatric patients with cancer or leukemia, showing both greater chronicity and extent of cutaneous and mucous membrane disease and prolonged viral excretion. Recurrent varicella or zoster occurred frequently in HIV-infected children and correlated with depletion of CD4-lymphocytes, but not anti-varicella antibodies (68). Coneenital varicella svndrome A recent report revealed that 24% of the offspring of women who contract varicella infection during pregnancy have children with serologic or clinical evidence of intrauterine varicella infection (69). Ocular findings in the congenital varicella syndrome include retinitis, optic disc atrophy and hypoplasia, congenital cataract and Horner’s syndrome (70). Zoster ophthalmicus in the immunocomDromised There is a direct correlation between increasing age and the incidence of zoster, with early studies showing peak occurrence during the seventh decade of life (71). This may reflect declining cell mediated immunity with age (72). Humoral immune responses to varicella-zoster also fall with increasing age (72), but zoster can occur despite the presence of high antibody tites (73) and is not more prevalent or severe in aggamaglobulinemicpatients (74). Zoster is both more common and serious in adults and children with compromised cellular immunity. There are reports of unilateral and bilateral zoster ophthalmicus in patients 8-14 days after childbirth (75,76), a condition in some ways immunologicallyanalogous to allograft tolerance. The incidence of zoster is elevated in patients with malignancy, organ transplants and AIDS. The reported incidence of zoster is 1-3% amongst patients with solid tumors, 7-9% with non-Hodgkin’s lymphoma and 13-15% with Hodgkin’s disease, of which 1530% will disseminate (20). Cutaneous dissemination appears 4 to 11days after localized zoster in 6 to 26% of patients, depending on the degree of cellular impairment. Ocular, visceral or neurologic involvement accompanies half of those with cutaneous dissemination. Ocular manifestation of varicella zoster include scleritis and episcleritis, dendritiform and stromal keratitis, neurotrophic keratitis, corneal scarring and vascularization, anterior uveitis, iris atrophy, and retinitis consistent with the Acute Retinal Necrosis (ARN) syndrome (77). In patients with malignancy, there appears to be a
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correlation with localized zoster and the staging of malignancy. In a prospective study, suppression of cell mediated immunity to zoster preceded each episode of zoster reactivation in patients with lymphoma (78). Local factors are also likely to be involved, since zoster appears to occur more frequently in areas of regionalized tumor and/or irradiation. Dissemination also is more common in advanced stages of malignancy (79). The primary immune response to varicella in children who contracted chickenpox prior to the diagnosis of acute lymphocytic leukemia (ALL), appears to provide immunologic protection against later development of zoster, as compared to zoster following varicella infection in children under treatment for leukemia. Varicella zoster virus seropositive children under treatment for leukemia are nearly 30 times more likely to develop zoster then healthy children (80). The dampened primary immune response to varicella in children treated for ALL who later develop zoster, may parallel the mechanism underlying zoster in infants who contracted chickenpox in utero or in the neonatal period. There are notable differences between the reactivation of herpes simplex virus and varicella zoster virus following organ and bone marrow transplantation. Following bone marrow or cardiac transplantation, HSV recurrence occurs at an earlier median time (one month for HSV versus five months for zoster). Lymphocyte transformation to varicella-zosterantigens is depressed for up to 100 days after transplantation, whereas HSV responses are maximally depressed immediately after transplantation, paralleling the time of recurrence for each virus (81,82). The use of anti-thymocyteglobulin, but not the occurrence of graft-versus-hostdisease, was associated with further depression of the lymphocyte response to zoster. Recovery of the lymphocyte transformation response to HSV and varicella-zosterwas associated with the reactivation of each virus, respectively, suggesting that immunologic responsiveness was dependent upon active virus infection. In summary, the lymphocyte transformation response to HSV and varicella zoster have different temporal sequences and are generally predictive of specific recurrent herpesvirus infection following transplantation. Zoster ophthalmicus is frequently an early or initial event followingHIV infection (82-84). It may be of predictive value for HIV infection in young individuals, and appears to predict an increased risk for the development of
AIDS (84-86). In one study, AIDS occurred with a 23% incidence within 2 years of zoster and 46%within 4 years. In a study in New York City (82), 61% of patients 15 to 44 years of age with zoster ophthalmicus were distinguished by AIDS- high risk factors, altered T-cell subsets, and polyclonal increases in serum gammaglobulin. In contrast, no one with zoster ophthalmicus over 45 years of age was identified to be at high risk for HIV. Within the high risk group, 21% developed AIDS over a 2 year period with a 14%mortality. In an African study (86), 23% of HIVseropositive patients with zoster experienced recurrence of zoster, a recurrence rate similar to lymphoma patients, as compared with none in the seronegative group. Zoster ophthalmicus in HIV-infected individuals frequently manifests severe and protracted cutaneous lesions (83,84),and is more commonly associated with ocular complications, such as keratitis and anterior uveitis (82). Zoster virus was recovered as late as 11 weeks after the onset of chronic, active dendritiform zoster keratitis with mild stromal haze in an AIDS patient (87). The lesion was not responsive to oral acyclovir or topical trifluridine, but resolved with acyclovir ointment. Measurable circulating alpha interferon inhibitors have been demonstrated in patients with zoster who are at high risk for AIDS (88). There have also been recent reports of acyclovir-resistant strains of varicella zoster recovered from AIDS patients with recurrent zoster keratouveitis and skin lesions, following chronic acyclovir therapy (89,90). Reinfection with varicella-zoster virus in the immunocommomised Whereas subclinical reinfection with varicella may occur, as evidenced serologically, second cases of chickenpox are uncommon. However, varicella following reinfection has been reported in immunocompromised patients after nosocomial exposure to an index case (91) and in patients with chronic granulomatous disease (92), a phagocytic disorder. CONCLUSIONS The immune response appears to afford a dynamic interplay in the life cycle of herpesvirus infections. Specific cellular immunity is paramount in control of viral reactivation, and may play a dialectical role in enhancing lesion formation, while controlling viral spread. Humoral immune responses may influence the establishment of latency and ameliorate lesion formation, but it is unclear 91
Current Eye Research whether the latter occurs via viral neutralization or through combined cellular mechanisms (e.g. antibody-dependent cellular cytotoxicity).
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ACKNOWLEDGEMENTS Supported in part by Public Health grant EY08143 from the National Eye Institute, National Institutes of Health. Dr. Pepose is the Research to Prevent Blindness Olga Keith Wiess Scholar. REFERENCES 1. Sullender, W.M., Miller, J.L., Yasukawa, L.L., Bradley, J.S., Black, S.B., Yeager, AS. and Arvin, A.M. (1987) Humoral and cell-mediated immunity in neonates with herpes simplex virus infection. J. Infect. Dis. 155.28-37. 2. Chilmonczyk, B.A., Levin, M.J., Duffy, R. and Hayward, A.R. (1985) Characterization of the human newborn response to herpesvirus antigen. J. Immunol, -9134 4184-4188. 3. Burchett, S.K., Westall, J., Mohan, K., Corey, L. and Wilson C.B. (1986) Ontogeny of neonatal mononuclear cell transformation and interferon gamma production after herpes simplex virus stimulation. Clin. Res. 34, 129. 4. Brick, D.C., Oh, J.O. and Sicher, S.E. (1981) Ocular lesions associated with dissemination of type 2 herpes simplex virus from skin infection in newborn rabbits. Invest. Ophthalmol. Vis. Sci. 681-688. 5. Nahmias, A.J., Visintine, A.M., Caldwell, D.R. and Wilson, L.A. (1976) Eye infections with herpes simplex viruses in neonates. Surv. Ophthalmol. 2 l , 100-105. 6. el Azazi, M., Malm, G. and Forsgren, M. (1990) Late ophthalmologic manifestations of neonatal herpes simplex virus infection. Am. J. Ophthalmol. 109, 1-7. 7. Metcalf, J.F. and Kaufman, H.E. (1976) Herpetic stromal keratitis-evidence for cell mediated immunopathogenesis.Am. J. Ophthalmol. 82,827834. 8. Rager-Zisman, B., Quan, P.C., Rosner, M., Moller, J.R. and Bloom, B.R. (1987) Role of NK cells in protection of mice against herpes simplex virus-1 infection. J. Immunol. 138,884-888. 9. Biron, C.A., Byron, K.S. and Sullivan, J.L. (1989) Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731-1735. 10. Kohl, S., West, M.S., Prober, C.G., Sullender, W.M., Loo, L.S. and Arvin, A.M. (1989) Neonatal antibodydependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. J. Infect. Dis. 100,770776. 11. Metcalf, J.M., Koga, J., Chattejee, S. and Whitley, R.J. (1987) Passive immunization with monoclonal antibodies against herpes simplex virus glycoproteins
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Anderson, H.Z. (1975) Herpesvirus hominis infections in renal transplant recipients. Scand. J. Infect. Dis. Z, 11-19. Pass, R.F., Whitley, R.J., Whelchel, J.D., Diethelm, A.G., Reynolds, D.W. and Alford, C.A. (1979) Identification of patients with increased risk of infection with herpes simplex virus after renal transplantation. J. Infect. Dis. 140.487-492. Howcroft, M.J. and Breslin, C.W. (1981) Herpes simplex keratitis in renal transplant recipients. Can. Med. Assoc. J. 124,292-294. Easty, D.L. (1977) Manifestations of immunodeficiency diseases in ophthalmology. Trans. 9 8-17. Ophthal. SOC.U.K. -7 Hirst, L.W., Jabs, D.A., Tutschka, P.J., Green, W.R. and Santos, G.N. (1983) The eye in bone marrow transplantation. I. Clinical study. Arch. Ophthalmol. 101,580-584. Jack, M.K. and Hicks, J.D. (1981) Ocular complications in high-dose chemoradiotherapy and marrow transplantation. Ann. Ophthalmol. J& 709711. Pass, R.F., Long, W.K., Whitley, R.J., Soong, S.-J., Diethelm, A.G., Reynolds, D.W. and Alford, C.A., Jr. (1978) Productive infection with cytomegalovirusand herpes simplex virus in renal transplant recipients: Role of source of kidney. J. Infect. Dis. 137.556-563. Rand, K.H. Rosmussen, LE., Pollard, R.B., Arvin, A. and Merigan, T.C. (1976) Cellular immunity and herpesvirus infections in cardiac-transplant patients. N. Engl. J. Med. 296, 1372-1377. Foster, A. and Sommer, k (1987) Corneal ulceration, measles, and childhood blindness in Tanzania. Br. J. Ophthalmol. 331-343. Liesegang, T.J. (1989) Epidemiology of ocular herpes simplex. Natural history in Rochester, MN, 1950 through 1982. Arch. Ophthalmol. 107.1160-1165. Amman, A.J. and Hong, R. (1973) Cellular immunodeficiencydisorders. In "Immunologic Disorders in Infants and Children", (eds. Stiehm E.R. and Fulgineti V.A.). Pp. 156-171. W.B. Saunders Co., Philadelphia. Fan, C.C., Shimomura, Y.,Inoue, Y.,Watanabe, H., Iwaski, N., Matsuda, M.,Manabe, R., Imara, M., Harada, S. and Yanaghi, K (1989) A case of simultaneous bilateral herpetic epithelial keratitis. Jpn. J. Ophthalmol.-33 120-124. Holland, G.N., Pepose, J.S. and Dinning, W.J. (1989) Ophthalmic disorders associated with selected primaq and acquired immunodeficiencydiseases. In "Duane's Clinical Ophthalmology", (eds. Tasman, W.and Jaeger, E.A.). Pp. 1-21. J.B. Lippincott, Philadelphia. Hegab, S.M., Sheriff, S.M.M., El-Aasar, E.S.M.and Lashin, E.Z. (1989) Herpetic stromal keratitis in congenital dysgamma globulinemia. Cornea, 5,102105. Shuler, J.D., Engstrom, R.E. and Holland, G.N. (1989) External ocular disease and anterior segment disorders associated with AIDS. Int. Ophthalmol. Clin. 29 98-104.
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68. Jura, E., Chadwick, E.G., Josephs, S.H., Steinberg, S.P., Yogev, R., Gershon, A.A., Krasinski, K.M. and Borkowsky, W. (1989) Varicella-zoster virus infections in children infected with human immunodeficiency virus. Ped. Infect. Dis. J. 8,586-590. 69. Paryani, S.G. and Arvin, A.M. (1986) Intrauterine infection with varicella-zoster virus after maternal varicella. N. Engl. J. Med. 314,1542-1545. 70. Lambert, S.R., Taylor, D., Kriss, A., Holzel, H. and Heard, S. (1989) Ocular manifestations of the congenital varicella syndrome. Arch. Ophthalmol. 107, 52-56. 71. Ragozzino, M.W., Melton, L.J. 111, Kurland, L.T., Chu, C.P. and Perry, H.O. (1982) Population-based study of herpes zoster and its sequelae. Medicine, 61,310-316. 72. Burke, B.L., Steele, R.W., Beard, O.W., Wood, J.S., Cain, T.D. and Marmer, D.J. (1982) Immune responses to varicella-zoster in the aged. Arch. Intern. Med. 142,291-293. 73. Brunell, P.A., Gershon, A.A., Uduman, S.A. and Steinberg, S. (1975) Varicella-zoster immunoglobulins during varicella, latency and zoster. J. Infect. Dis. 132, 49-54. 74. Straus, S.E. Ostrove, J.M., Inchauspk, G., Felser, J.M., Freifeld, A, Croen, K.D. and Sawyer, M.A. (1988) Varicella-zoster virus infections. Biology, natural history, treatment, and prevention. Ann. Int. Med. 108.221-237. 75. Edgerton, A.E. (1945) Herpes zoster ophthalmicus. Report of cases and review of literature. Arch. Ophthalmol. 34,40-62, 114-153. 76. Yamada, K, Harjasaka, S., Yamamoto, Y. and Setogawa, T. (1990) Cutaneous eruption with or without ocular complications in patients with herpes zoster involving the trigeminal nerve. Graefe’s Arch. Clin. Exp. Ophthalmol. 228, 11-14. 77. Jabs, D.A., Schachat, AP., Liss, R., Knox, D.L. and Michels, R.G. (1987) Presumed varicella zoster retinitis in immunocompromised patients. Retina, 2, 913. 78. Arvin, A.M., Pollard, R.B., Rasmussen, L.E. and Merigan, T.C. (1980) Cellular and humoral immunity in the pathogenesis of recurrent herpes viral infections 869-878. in patients with lymphoma. J. Clin. Invest. 79. Stevens, D.A. and Merigan, T.C. (1980) Zoster immune globulin prophylaxis of disseminated zoster in compromised hosts: a randomized trial. Arch. Intern. Med.140, 52-54. 80. Grose, C. and Giller, R.H. (1988) Varicella-zoster virus infection and immunization in the healthy and the immunocompromised host. CRC Crit. Rev. Oncol. Hematol. 8,27-64. 81. Meyers, J.D., Flournoy, N. and Thomas, E.D. (1980) Cell-mediated immunity to varicella-zoster virus after allogeneic marrow transplantation. J. Infect. Dis. 141, 479-487. 82. Sandor, E.V., Millman, A , Croxson and T.S., Mildvan, D. (1986) Herpes zoster ophthalmicus in patients at risk for the acquired immune deficiency syndrome
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(AIDS). Am. J. Ophthalmol. 201, 153-155. Kestelyn, P., Stevens, A.M., Bakkars, D., Rouvroy, D. and Van de Perre, P. (1987) Severe herpes zoster ophthalmicus in young African adults: a marker for HTLV-I11seropositivity. Br. J. Ophthalmol. 7 l , 806809. Cole, E.L., Meisler, D.M., Calabrese, L.H., Holland, G.N., Mondino, B.J. and Conant, M.A. (1984) Herpes zoster ophthalmicus and acquired immune deficiency sundrome. Arch. Ophthalmol. 102, 1027-1029. Melbye, M., Grossman, R.J., Goedert, J.J., Eyster, M.E. and Biggar, R.J. (1987) Risk of AIDS after herpes zoster. Lancet, & 728-730. Colebunders, R., Mann, J.M., Francis, H., Kapita, B., Izaley, L,Ilwaya, M., Kakonde, N., Quinn, T.C., Curran, J.W. and Piot, P. (1988) Herpes zoster in African patients: a clinical predictor of human immunodeficiency infection. J. Infect. Dis. 157,314318. Engstrom, R.E. and Holland, G.N. (1988) Chronic herpes zoster virus keratitis associated with the acquired immunodeficiency syndrome. Am. J. Ophthalmol. 105.556-559. Ambrus, J.L. Poiesz, B.J., Lillie, M.A., Stadler, I., Di Berardino, L.A. Chadha, K.C. (1989) Interferon and interferon inhibitor levels in patients infected with varicella-zoster virus, acquired immunodeficiency syndrome-related complex, or Kaposi's sarcoma, and in normal individuals. Am. J. Med. 87,405-407. Pahwa, S., Biron, K., Lim, W., Swenson, P., Kaplan, M.H., Sadick, N., Pahwa, R. (1988) Continuous varicella-zoster virus infection associated with acyclovir resistance in a child with AIDS. JAMA, 260, 2879-2882. Jacobson, M.A., Berger, T.G., Fikrig, S., Becherer, P., Moohr, J.W., Stanat, S.C. and Biron, K.K. (1990) Acyclovir-resistant varicella-zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann. Int. Med. 112. 187-191. Junker, K. Amstorp, C., Nielsen, C.M. and Hansen, N.E. (1989) Re-infection with varicella-zoster virus in immunocompromised patients. Curr. Probl. Dermatol. l8,152-157. Kobayashi, S., Ichinohe, S., Okabe, N. and Tatsuzawa, 0.(1988) Varicella-zoster virus infection in chronic granulomatous disease. Ped. Infect. Dis. J. 2,809-810.
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Volume 10 supplement 1991
External ocular herpesvirus infections in immunodeficiency
Jay S.Pepose
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Departments of Ophthalmology and Visual Sciences and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
ABSTRACT Infections of the eye with members of the herpes family of viruses (e.g. HSV, CMV, VZV) are frequent manifestations of acquired and inherited defects in cell mediated immunity. Herpesvirus infections in the immunocompromised may reflect frequent viral reactivation from the latent state, as well as extensive productive infection of ocular structures following reactivation or primary infection. A review of experimental and clinical studies of both acquired and inherited immune dysfunction implicates specific immune mechanisms influencing the establishment of latency, viral reactivation and the control of active viral replication in ocular tissues. INTRODUCTION The immune system may have a profound effect on the biology of herpetic infections at several stages (Figure 1): (1) the acute primary infection, (2) the initial spread of virus and the establishment of latency, (3) reactivation from latency, (4) control of active recurrent infection, ( 5 ) protection from exogenous reinfection with new viral strains. A review of common external ocular herpetic disease in clinical and experimental forms of acquired and inherited immunodeficiency points to specific immunologic mechanisms affecting each of these stages. HERPES SIMPLEX KERATITIS IN THE IMMUNOCOMPROMISED Primaw infection Primary herpes simplex virus (HSV) infection can cause extensive ocular and systemic morbidity in the immunocompromised, such as neonates and individuals with acquired or inherited defects in cellular immunity. It is well established that neonates have compromised cellular immune function. Most newborns with HSV infection have no detectable T-lymphocyte responses to HSV until 2-4 weeks after the onset of infection (1,2) This is thought to reflect a low responder cell frequency rather than impairment in monocyte processing. In addition, infected
newborns have decreased production of alpha interferon in response to HSV antigen compared to adults with primary HSV (l), as well as decreased production of gamma interferon after HSV stimulation (3). Whereas 80% of neonatal HSV infection is caused by HSV type 2, both HSV types 1 and 2 have been associated with neonatal keratitis. HSV-infected peripheral blood mononuclear cells appear to play a major role in disseminating the virus in a rabbit model of neonatal ocular herpes simplex infection (4). Deficiencies in cellular immunity and lymphokine generation described in the previous paragraph may influence both the nature of neonatal herpetic keratitis and the likelihood of viral dissemination. In a study of ophthalmic manifestations of neonatal HSV, Nahmias et a1 (5) reported a 7% incidence of keratitis (19/297 patients examined). A study of late ophthalmic signs of neonatal HSV (6) revealed a 6% incidence of keratitis in patients with disseminated disease, all with resulting vision of 20/40 or better. This relatively good long term vision following neonatal HSV keratitis could reflect a paucity of cells infiltrating neonatal corneal lesions, as a result of impaired cellular immunity. Much of the early corneal opacification in these patients may reflect reversible corneal edema, rather than stromal inflammation. This may be analogous to the observation that congenitally athymic (nude) mice, unlike their euthymic littermates, failed to develop stromal keratitis. Stromal disease could be restored by reconstitution with T-cells from HSV-immune animals (7). Natural killer (NK) cell function is also decreased in neonates. NK cells have been demonstrated to play a protective role against the development of fatal HSV infections in mice (8). A 13 year old girl with complete and specific lack of natural killer (NK) cells developed a variety of life threatening primary herpes virus infections,
Received on August 3 , 1990: acceptcd on October 2 5 , 1990
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Figure 1. The immune res onse may influence the biology of herpes simplex virus in ection at several discrete phases.
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emphasizing the critical protective role of NK cells in limiting disseminated infection (9). Transplacental transfer of antibodies to the neonate, while not totally protective, may serve to ameliorate HSV infection. For example, antibody-dependent cellular cytotoxicity antibody levels or high levels of neutralizing antibodies are independently associated with absence of HSV dissemination (10). Several investigators have demonstrated that passive transfer of antiherpes antibody will prevent HSV stromal keratitis in mice following primary corneal inoculation (11-13). Shimeld et a1 (14) and Tullo and co-workers (15) demonstrated that the effect of passive immunization does not limit the severity of corneal epithelial disease, but restricts viral spread within the nervous system with consequent transport back to the eye. The protective role of antibody could also explain the more widespread dissemination of HSV in mice with severe combined immunodeficiency (SCID), in which both T and B-cell function are severely diminished, compared to congenitally athymic mice (16). Several studies also suggest an active role for antibody to HSV in the establishment and maintenance of latency. Passive transfer of antiviral antibodies reduces the establishment of lytic and latent infection in non-ophthalmic portions of the trigeminal ganglia following corneal inoculation (14,15). In a modified murine model of HSV latency and reactivation, we have found that passive immune transfer tends to drive the virus directly into neuronal latency (16). In experiments transplanting latently
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infected ganglia in millipore filters to naive or immune mice, Stevens and Cook (17) further implicated a role for antiviral IgG in the maintenance of the latent state in neurons. Clinically, however, there appears to be no correlation between neutralizing antibodies and the incidence of recurrent disease (18). Following primary herpetic keratitis in inbred mice, a marked variation in the number of latently infected cells was noted between inbred strains (19). It has not, however, been determined which specific immune mechanisms contribute to or underlie this genetic difference in susceptibility to the establishment of latency. HSV reactivation Herpes simplex virus (HSV) reactivation appears to be more frequent and often, more serious, in patients with defects in cell mediated immunity (20) (e.g. organ transplant recipients, patients given cytotoxic agents for malignancy, malnourished individuals, burn patients, those with skin conditions such as eczema, or inherited cellular immune defects). However, most frequent signs of reactivation in these patients involve nasolabial disease. The specific incidence of herpetic keratitis or asymptomatic viral shedding in tears (21) of the immunocompromised has not been systematically studied. Various systemic immunosuppressive regimens have been shown to induce reactivation of latent HSV in rabbits (22,23) and mice (24-27), with recovery of virus in the tear film. When accompanied by ultraviolet irradiation, recurrent corneal lesions have been frequently noted in immunosuppressed rabbits (22) and mice (26). While topical corticosteroids may not alter the incidence of HSV reactivation in animals (B),they increase the duration of viral shedding once reactivation has occurred. With so many diverse stimuli capable of triggering HSV reactivation from the ganglia, the mechanisms underlying reactivation by immunosuppressive drugs may be complex. T-cells have been demonstrated in rabbit trigeminal ganglia following the acute infection (29) and mononuclear cells are prominent in the trigeminal ganglia of small proportion of NIH mice following reactivation (16). However, there has been no direct correlation shown between viral reactivation and local cellular infiltrates within the ganglia. Immunosuppressive drugs that induce HSV reactivation may not necessarily act via a conventional immunologic pathway alone. Recent studies have shown that during
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Current Eye Research herpetic latency, viral transcripts are made from the opposite strand of DNA coding for the immediate early gene, ICPO (30-32). Mutant strains of HSV lacking the genetic information coding for latency associated transcripts (LATs) reactivate with reduced efficiency (33,34), implicating an important role for LATs in facilitating reactivation. Other studies have shown that many drugs that modulate cyclic AMP levels may influence HSV reactivation in vivo (35). One factor that may link these two findings is the demonstration of a cyclic AMP responsive element within the promoter region of the LATs gene and the presence of a degenerate CAMPresponsive element in the ICPO promoter (36) -- two genes central to viral reactivation. As a precedent that immunosuppressive agents may affect viral transcription, dexamethasone has been shown to influence the expression of the latencyrelated gene of bovine herpesvirus 1(37). Another way in which immunosuppression may increase the frequency of recurrent HSV lesions, involves the hypothesis of Hill and Blyth (38). They proposed that infectious particles could be produced periodically in the ganglia during latency and transported to the corneal nerve endings via retrograde axoplasmic flow. It is possible that immunosuppression does not so much influence the frequency of HSV reactivation at the ganglionic level, but rather the immune response at the periphery causing exacerbations of an otherwise limited or totally asymptomatic infection. For example, following immunosuppression with cyclosporine A, rabbits developed more extensive lesions (39), and shed virus for a longer duration in a model of primary herpes keratitis (39,40). A review of the literature reveals numerous anecdotal reports of HSV keratitis amongst patients with acquired and inherited forms of cell mediated immunodeficiency. Several studies cite cases of keratoconjunctivitiswith chronic viral shedding, ulceration and/or perforation, frequently occurring within one month of renal (41-44) or bone marrow transplantation (49, or in association with graftversus-host disease (46). Herpetic recurrence correlated with the dose of immunosuppression and the time of greatest defects in lymphocyte transformation and interferon production in response to HSV antigens (47,48). Chronic and prolonged ulcerative and stromal HSV keratitis has been also associated with other forms of predominantly depressed cellular immunity indicating the Wiskott-Aldrich
syndrome (49), severe atopic eczema (44,50) or in association with measles, malaria and malnutrition in children (51). Corneal disease in these children is often bilateral and may be a prelude to viral dissemination and death. Similarly,bilateral recurrent HSV keratitis, which is far rarer than bilateral primary HSV keratitis, has been reported in an adult with alcoholic hepato-cirrhosis, chronic anemia and bronchitis (52), who was likely immunosuppressed. In contrast to disorders affecting predominantly cellular immunity, primary humoral immunodeficiencies (e.g. Xlinked aggamaglobulinemia,IgA deficiency) does not appear associated with an increased incidence of recurrent herpetic infection nor unusual pathology once reactivation has occurred (53). A single case report of recurrent herpes simplex stromal keratitis in congenital dysgammaglobulinemia showed a good, typical response to conventional antiviral therapy with low dose topical steroids, resulting in resolution with minimal scarring (54). Control of recurrent infection Once reactivation has occurred, herpes simplex keratitis may have atypical features in patients with cellular immunodeficiency. It is unclear whether AIDS patients overall have a higher incidence of HSV keratitis than in immunocompetent individuals. However, once reactivation has occurred in an individualwith AIDS, the course of HSV keratitis is generally prolonged and recurrences are frequent (55). Epithelial disease has an unusual predilection for peripheral cornea and limbus and average healing time with topical antiviral therapy is three weeks. One AIDS patient developed HSV epithelial keratitis refractory to antiviral therapy, which healed after three weeks of topical recombinant interferon-alpha 2a (56). Stromal disease in these patients is uncommon (55), probably reflecting their inability to mount an adequate cell mediated immune response. Similar features of HSV keratitis have been noted in other patients with deficient cellular immunity, such as transplant recipients (41,44). A reduced incidence of HSV stromal keratitis has been demonstrated in susceptible immunogenetic strains of mice after pretreatment with cyclophosphamide (27) and by other forms of depressed delayed type hypersensitivity (57,58). Whether a decrease in the number or function of migratory local immune cells, such as Langerhans cells, also plays a modulatory role in ocular lesion formation (59) in
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immunocompromisedpatients and experimental animals deserves further study. OCULAR VARICELLA-ZOSTER VIRAL INFECTIONS IN THE IMMUNOCOMPROMISED Primarv infections Whereas primary varicella generally runs a benign course in the immunocompetent, it can be a cause of grave morbidity and mortality in the immunocompromised. Ocular signs are generally confined to vesicular lesions of the conjunctiva, rare dendritic figures or disciform keratitis. Patients with deficient cell mediated immunity are at high risk (20-35%)for visceral dissemination to lung, liver or brain with a 7-30%mortality rate (60). High risk patients include children with acute leukemia, non-Hodgkin’s lymphoma, solid tumors, Hodgkin’s disease and after bone marrow transplantation (61). Dissemination was more common in patients with lymphocyte counts below 500/mm2 on the first day of infection (60) and the risk was diminished in patients when chemotherapy was halted during the varicella incubation period. As compared to immunocompetent children, children with cancer developed less antibody to certain varicellazoster glycoproteins, but not to others (62). In contrast, Tlymphocyte function plays a pivotal role in recovery from primary infection and in prevention of subsequent reactivation. Reduced lymphocyte proliferation to varicellazoster has been associated with chemotherapy for leukemia and may be of predictive value for patients at risk for reactivation. Monocyte mediated antigen presentation appears intact, while virus-specificlymphocyte numbers decline and may underlie the immunodeficiency to varicella in these children (63). Fatal attacks of varicella have also been reported in patients with primary combined immunodeficiencies including Nezeloff syndrome and cartilage-hair hypoplasia (64). Varicella-zoster immune globulin may ameliorate or prevent varicella in the immunocompromised, but has no effect on zoster infection or dissemination (65). Live, attenuated varicella vaccine (Oka Strain) protects high risk immunosuppressed individuals who have been exposed to varicella or zoster (66). However, immunity may quickly wane in these patients, and vaccine induced rashes are common. Zoster has been reported following vaccination, and can be due to either reactivation of the vaccine strain or to exogenous infection (67). 90
Varicella in children with HIV infection manifests differently than in pediatric patients with cancer or leukemia, showing both greater chronicity and extent of cutaneous and mucous membrane disease and prolonged viral excretion. Recurrent varicella or zoster occurred frequently in HIV-infected children and correlated with depletion of CD4-lymphocytes, but not anti-varicella antibodies (68). Coneenital varicella svndrome A recent report revealed that 24% of the offspring of women who contract varicella infection during pregnancy have children with serologic or clinical evidence of intrauterine varicella infection (69). Ocular findings in the congenital varicella syndrome include retinitis, optic disc atrophy and hypoplasia, congenital cataract and Horner’s syndrome (70). Zoster ophthalmicus in the immunocomDromised There is a direct correlation between increasing age and the incidence of zoster, with early studies showing peak occurrence during the seventh decade of life (71). This may reflect declining cell mediated immunity with age (72). Humoral immune responses to varicella-zoster also fall with increasing age (72), but zoster can occur despite the presence of high antibody tites (73) and is not more prevalent or severe in aggamaglobulinemicpatients (74). Zoster is both more common and serious in adults and children with compromised cellular immunity. There are reports of unilateral and bilateral zoster ophthalmicus in patients 8-14 days after childbirth (75,76), a condition in some ways immunologicallyanalogous to allograft tolerance. The incidence of zoster is elevated in patients with malignancy, organ transplants and AIDS. The reported incidence of zoster is 1-3% amongst patients with solid tumors, 7-9% with non-Hodgkin’s lymphoma and 13-15% with Hodgkin’s disease, of which 1530% will disseminate (20). Cutaneous dissemination appears 4 to 11days after localized zoster in 6 to 26% of patients, depending on the degree of cellular impairment. Ocular, visceral or neurologic involvement accompanies half of those with cutaneous dissemination. Ocular manifestation of varicella zoster include scleritis and episcleritis, dendritiform and stromal keratitis, neurotrophic keratitis, corneal scarring and vascularization, anterior uveitis, iris atrophy, and retinitis consistent with the Acute Retinal Necrosis (ARN) syndrome (77). In patients with malignancy, there appears to be a
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correlation with localized zoster and the staging of malignancy. In a prospective study, suppression of cell mediated immunity to zoster preceded each episode of zoster reactivation in patients with lymphoma (78). Local factors are also likely to be involved, since zoster appears to occur more frequently in areas of regionalized tumor and/or irradiation. Dissemination also is more common in advanced stages of malignancy (79). The primary immune response to varicella in children who contracted chickenpox prior to the diagnosis of acute lymphocytic leukemia (ALL), appears to provide immunologic protection against later development of zoster, as compared to zoster following varicella infection in children under treatment for leukemia. Varicella zoster virus seropositive children under treatment for leukemia are nearly 30 times more likely to develop zoster then healthy children (80). The dampened primary immune response to varicella in children treated for ALL who later develop zoster, may parallel the mechanism underlying zoster in infants who contracted chickenpox in utero or in the neonatal period. There are notable differences between the reactivation of herpes simplex virus and varicella zoster virus following organ and bone marrow transplantation. Following bone marrow or cardiac transplantation, HSV recurrence occurs at an earlier median time (one month for HSV versus five months for zoster). Lymphocyte transformation to varicella-zosterantigens is depressed for up to 100 days after transplantation, whereas HSV responses are maximally depressed immediately after transplantation, paralleling the time of recurrence for each virus (81,82). The use of anti-thymocyteglobulin, but not the occurrence of graft-versus-hostdisease, was associated with further depression of the lymphocyte response to zoster. Recovery of the lymphocyte transformation response to HSV and varicella-zosterwas associated with the reactivation of each virus, respectively, suggesting that immunologic responsiveness was dependent upon active virus infection. In summary, the lymphocyte transformation response to HSV and varicella zoster have different temporal sequences and are generally predictive of specific recurrent herpesvirus infection following transplantation. Zoster ophthalmicus is frequently an early or initial event followingHIV infection (82-84). It may be of predictive value for HIV infection in young individuals, and appears to predict an increased risk for the development of
AIDS (84-86). In one study, AIDS occurred with a 23% incidence within 2 years of zoster and 46%within 4 years. In a study in New York City (82), 61% of patients 15 to 44 years of age with zoster ophthalmicus were distinguished by AIDS- high risk factors, altered T-cell subsets, and polyclonal increases in serum gammaglobulin. In contrast, no one with zoster ophthalmicus over 45 years of age was identified to be at high risk for HIV. Within the high risk group, 21% developed AIDS over a 2 year period with a 14%mortality. In an African study (86), 23% of HIVseropositive patients with zoster experienced recurrence of zoster, a recurrence rate similar to lymphoma patients, as compared with none in the seronegative group. Zoster ophthalmicus in HIV-infected individuals frequently manifests severe and protracted cutaneous lesions (83,84),and is more commonly associated with ocular complications, such as keratitis and anterior uveitis (82). Zoster virus was recovered as late as 11 weeks after the onset of chronic, active dendritiform zoster keratitis with mild stromal haze in an AIDS patient (87). The lesion was not responsive to oral acyclovir or topical trifluridine, but resolved with acyclovir ointment. Measurable circulating alpha interferon inhibitors have been demonstrated in patients with zoster who are at high risk for AIDS (88). There have also been recent reports of acyclovir-resistant strains of varicella zoster recovered from AIDS patients with recurrent zoster keratouveitis and skin lesions, following chronic acyclovir therapy (89,90). Reinfection with varicella-zoster virus in the immunocommomised Whereas subclinical reinfection with varicella may occur, as evidenced serologically, second cases of chickenpox are uncommon. However, varicella following reinfection has been reported in immunocompromised patients after nosocomial exposure to an index case (91) and in patients with chronic granulomatous disease (92), a phagocytic disorder. CONCLUSIONS The immune response appears to afford a dynamic interplay in the life cycle of herpesvirus infections. Specific cellular immunity is paramount in control of viral reactivation, and may play a dialectical role in enhancing lesion formation, while controlling viral spread. Humoral immune responses may influence the establishment of latency and ameliorate lesion formation, but it is unclear 91
Current Eye Research whether the latter occurs via viral neutralization or through combined cellular mechanisms (e.g. antibody-dependent cellular cytotoxicity).
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