艾滋病和眼部并发症
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首席医学网
2009年03月17日 11:06:38 Tuesday
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作者：谭穗懿, 刘叔文，姜世勃 作者单位：1510515中国广东省广州市，南方医科大学药学院；2NY 10065美国纽约市纽约血液中心LFK研究所病毒免疫学研究室
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【摘要】 采用高效抗逆转录病毒疗法(HAART)后，由于免疫功能恢复和机会性感染的减少，极大地改变了艾滋病毒(HIV)感染者眼部疾病的病程及病史。然而，即使在HAART时代，眼部并发症仍然是艾滋病的临床特征之一，在发展中国家中尤其如此，而绝大多数HIV阳性病患者生活在发展中国家或地区。由于缺乏检验设备和经验、卫生条件差、微生物环境不同及缺乏有效的治疗，生活在发展中国家和地区的HIV感染者眼部并发症的特征与发达地区的艾滋病患者大不相同。因此，治疗发展中国家和地区HIV感染者的眼部并发症，具有更大的挑战性。此外，成人和儿童艾滋病患者眼部并发症也是不同的。与此同时，HAART的副作用也给眼部并发症带来了新的危险因素。所以，相关的研究应给予更多的关注。
【关键词】 艾滋病毒；眼部并发症；视网膜病变；肿瘤；机会性感染；高效抗逆转录病毒疗法
INTRODUCTION
Human immunodeficiency virus (HIV) continues to be one of the most devastating evils that pose great threat to public health worldwide, especially in the developing countries, which amounts to more than 95% of global HIV infections. Being the most severe infected region, SubSaharan Africa accounts for more than two thirds of HIV infections and three quarters of all AIDS deaths in 2007. The HIV epidemic in South and Southeast Asia is among the second largest in the world, India making up half of the HIVinfected population in Asia (Figure 1).
Complications commonly involve the eyes in HIVinfected persons. Autopsy revealed that up to 95% of AIDS patients have some form of ocular abnormalities[1]. Ocular lesions are varied and affect almost all parts of the eye. In the early stages of HIV infection, ophthalmic manifestations may be asymptomatic, thus hampering prompt medical attention and, ultimately, leading to a variety of tissuedestructive conditions, including visual impairment and even blindness. Since HIV has been isolated from retina, it is believed that ocular complication results either from a general decrease of host immunity or, more likely, direct ocular infection by HIV through the bloodaqueous barrier and/or bloodretinal barrier.
Ocular complication of HIV/AIDS differs from region to region. Most of the reports on ophthalmic manifestations of HIV infection come from developed countries, especially in the preHAART era. However, in recent years more and more cases and reports on ocular complication of HIV infection are being documented in developing countries, revealing an increasing attention and concern of the ocular status of HIV patients in these regions in which most of HIVpositive population live nowadays.
RISK PREDICTOR OF OCULAR COMPLICATIONS IN HIVPOSITIVE PATIENTS
The number of CD4 T cells which are the primary targets and reservoirs of HIV infection, serves as the key marker of the hosts immune competence to respond to opportunistic pathogens. Its been many years that CD4 T lymphocytes counts has been proved a reliable and important predictor of the risk for developing and indicator for managing ocular complications of HIV infection. Different ocular complica tions may develop at different CD4 threshold. However, CD4 threshold may not always be the absolute criterion for predicting ocular complications since reconstituted CD4+ lymphocytes due to HAART may fail to provide protective immunity. Some reports revealed that HIVpositive patients with CD4+ counts higher than 200 cells/μL developed cytomegalovirus retinitis. Table 1a Ophthalmic findings with HIV infection in some countries which have conducted surveys in the preHAART era（略）Table 1b Ophthalmic findings with HIV infection in some countries which have conducted surveys in the preHAART era（略）
Also, the incidence of ocular disorders correlates with the WHO clinical stage of HIV/AIDS. Stage 4 patients suffer the great chance to be affected. The prevalence of ocular manifestations in patients with stage 3 is greater than those with stages 1 and 2[2]. Some studies suggest that homosexuality may place HIV patients at higher risk for ocular problems[3].
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
Thus far, AIDS is not yet curable, and there is no effective vaccine for prevention. However, the introduction of HAART over the past decade has resulted in a dramatic reduction in the morbidity and mortality and an improved quality of life of HIV/AIDS patients. As a consequence of HAART, the pattern and nature history of ocular problems of HIV infection has significantly altered[4]. HAART usually consists of three different kinds of antiretroviral drugs, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors and protease inhibitors. The use of HAART has resulted in the ability of the host to regain immunity and suppress viral loads.Table 2a Ophthalmic findings with HIV infection in some countries which have conducted surveys in the HAART era（略）Table 2b Ophthalmic findings with HIV infection in some countries which have conducted surveys in the HAART era（略）
Some reports associated with ocular observation in HIVpositive patients in different countries both in preHAART and HAART era have been summarized (Table 1 and 2). Although different reports examined using different protocol, there is obviously a profound changing face of ophthalmic problems of HIV infection due to the availability of HAART. The incidence of ocular complication of HIVpositive patients has decreased from as high as 80% before the HAART era to less than 40% in the HAART era in general. Cytomegalovirus (CMV) retinitis and microvasculopathy continue to be the major types of ocular complications in HIV patients in the HAART era even with a significant declining incidence. However, we should keep in mind that despite the widespread use of HAART in developed countries, in many parts of the developing world, up to 80% of people infected with HIV who are in clinical need of treatment do not yet have access to antiretroviral drugs. Besides the cost of HAART, some factors such as restrictive licensing policies hamper the development and use of HAART in developing regions. Therefore, the ophthalmic manifestation of HIV infection in developing countries, especially in SubSaharan Africa, is characterized itself from that in developed countries by the higher incidence and more prevalence of opportunistic infections in the HAART era. Many factors, such as lack of effective antiviral therapies,lack of test facilities and experience, poor hygiene conditions, different microbiological environment, patients nutritional status, may contribute to this distinction. Table 3 Common ocular opportunistic pathogens and sites of infection in HIV/AIDS patients（略）
CYTOMEGALOVIRUS RETINITIS AND OTHER OPPORTUNISTIC INFECTIONS
Once the immune system of HIVinfected patients is weakened by either preexisting or newly infected pathogens, such as bacteria, fungi, viruses, parasites, spirochetes, and mycobacteria, these pathogens can be reactivated and spread to the eye via the bloodstream, causing acute or chronic, serious or indistinctive, ocular diseases. CMV retinitis is still one of the most serious opportunistic infection in HIV/AIDS even in the HAART era. Some opportunistic infections, such as varicella zoster virus, toxoplasmosis, are more prevalent in the developing regions, which may arise from complicated ecological, racial, nutritional and socioeconomic factors which favor the viral transmission and reactivation in HIVinfected patients. The common ocular opportunistic pathogens and sites of infection in HIV/AIDS patients were summarized in Table 3.
Cytomegalovirus Coinfection of cytomegalovirus (CMV), a herpes virus, is a major cause of morbidity and mortality of HIV/AIDS patients. The virus can be in a latent state in infected individuals, presumably for life. With immunodeficiency, dissemination and tissue destructive infection can occur. CMV causes a characteristic necrotizing retinitis with clinical symptoms of visual field defects, decreased visual acuity, retinal detachment, floaters and photophobia. CMV retinitis accounts for 75%85% of cytomegalovirus disease and over 90% of blindness in AIDS patients[5]. It usually develops when the CD4+ cell counts fall below 50 cells/μL. HIV patients with a low CD4+ cells may have the same incidence of CMV as those in the preHAART era. Periodic examinations are recommended for those with CD4+ counts below 100 cells/μL, especially if CMVantibody positive. Some studies suggest that HIV RNA blood level is also an important predictor of CMV retinitis since HIV can transactivate CMV[6]. In the preHAART era, CMV retinitis is less common in Africa than in North America and Europe, which may be the cause that HIV patients died before the development of CMV retinitis in the poor regions[7]. AIDS patients often die of tuberculosis which appears at an early stage of HIV infection in developing regions. Nowadays, HAART has most significantly changed the incidence, progression and management of CMVR by decreasing the incidence of CMV retinitis by 75%90%. However, CMV retinitis remains the most important issues in HIVpatients with over 30% prevalence in some developing regions due to the unavailability of HAART.
Varicella Zoster Virus Varicella zoster virus (VZV) is a common infection in humans. Once exposed to VZV, latency can persist throughout life. Reactivation of VZV in the trigeminal ganglion can result in herpes zoster ophthalmicus (HZO), which may be the initial manifestation of HIV infection. HZO affects 5%15% of HIVpositive patients[8]. Immunocompromised patients and older people are more prone to VZV reactivation[9]. Incidence of HZO is six times greater in HIV/AIDS patients than in healthy people. In Nigeria, herpetic eye disease constituted half of the ocular cases and there is strong association between HZO and HIV infection[10]. Studies found that over 60% patients with HZO are HIVpositive in Nigeria[11,12]. The anterior presentations in AIDSassociated HZO include, for example, conjunctivitis, scleritis, epithelial keratitis, stromal keratitis, uveitis, blepharitis, etc.[9] Treatment of HZO in AIDS patients usually starts with promptand aggressive intravenous antiviral treatment, followed by an oral maintenance regimen. However, when the infection continues and spreads to the posterior parts, necrotizing herpetic retinopathy (NHR) may occur. It is reported that 4%17% of HIVpositive individuals develop NHR after HZO. Acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) are the two distinct forms of NHR. Usually the former occurs in those with only mild immune deficiency and elevated CD4+ counts, while the latter happens in those who are severely immunosuppressed. However, both forms have been identified simultaneously in an AIDS patient[13]. PORN has a rapid and progressive course leading to devastating vision loss, which, in most cases, is difficult to treat[14]. Intravitreal injection with combined antiviral drugs may be more effective in treating this aggressive disease and quantitative measurements of VZV DNA from aqueous humor appear helpful in the management of PORN[14]. Table 4 Comparison of three common ocular tumors in HIV/AIDS patients（略）Table 5 Ophthalmic findings with pediatric HIV infection in some countries which have conducted surveys in the HAART era（略）
Molluscum Contagiosum Molluscum contagiosum (MC) virus is another opportunistic pathogen that can cause MC in HIVinfected patients. MC is a contagious disorder that can occur in both pediatric and adult HIV/AIDS patients, but it is more prevalent in children in undeveloped areas. A crosssectional hospital based study in Uganda showed that over 10% of pediatric HIV patients had MC[15]. MC virus commonly infects the eyelid, and, rarely, the conjunctiva, corneal and limbus[16]. Symptoms include chronic follicular conjunctivitis, corneal micropannus and epithelial keratitis[17]. MC is suggested to be a sign of advanced AIDS and appears in advanced HIV infection when CD4+ counts are less than 80 cells/μL[18,19]. Eyelid lesion can be treated as the first manifestation of AIDS[20]. The disease is more aggressive in AIDS patients with immunosuppression, and there is usually multiple lesion involvement[17,21]. No drug is effective in treatment of MC. Traditional treatments, such as local excision, laser or cryotherapy, can be applied to MC in AIDS patients. If treatment is not prompt enough, severe complications will ensue. Nevertheless, the high recurrence may make the original treatment a failure[21,22].
Ocular Toxoplasmosis Toxoplasma gondii is a common parasites infection in HIV/AIDS patients[23]. Ocular toxoplasmosis accounts for 1%3% infection in AIDS patients. Single or multiple lesion of retinitis may affect both eyes with massive areas of retinal necrosis. Combination therapy of pyrimethamine with sulfadiazine and/or clindamycin is effective and lifelong maintenance treatment is necessary to prevent recurrence. System evaluation is suggested once the ocular toxoplasmosis is defined due to the high incidence of concomitant CNS toxoplasmosis[24].
Ocular Tuberculosis Tuberculosis, a mycobacterial infection caused by Mycobacterium tuberculosis, has a higher incidence in AIDS patients than the general population, especially in developing region[25]. 46% of HIVpositive patients in the developing world are coinfected with tuberculosis and as many as 23% HIVtuberculosis coinfection patients had disseminated ocular tuberculosis[25,26]. Ocular tuberculosis can occur even with very high CD4+ cell counts. Regular ocular examination for ocular tuberculosis is necessary in HIV infected cases in the developing regions despite the relative high CD4+ counts and prescription of HAART.
Fungi Cryptococcosis is the most common fungal infection occurring in 5%10% of all AIDS patients[27]. Lungs and CNS are the two most common sites for cryptococcus infection. The fungi causing ocular infection in HIVpositive patients is believed to be the spread from the infected CNS. Cryptococcal encephalitis is one of the major causes of AIDS mortality. A SubSahara African study show that in Zimbabwe, 45% of meningitis in adults is cryptococcal, and cryptococcal meningitis is the third leading cause of death in HIV patients in rural Uganda. In Rwanda, 9% of patients with cryptococcal meningitis developed visual loss and sixth nerve palsy[28]. In the eyes, cryptococcal encephalitis frequently presents as papilledema, multifocal choroiditis, visual loss, optic nerve irruption and optic atrophy[29]. Not only can HIV invade the nervous system, but HIV1 gp41 ectodomain also plays a role in enhancing Cryptococcus neoformans invasion of human brain microvascular endothelial cells[30]. Nevertheless, patients can regain their visual function follow optimal therapy.
Bacteria The differences in ocular bacterial flora between HIVinfected subjects and healthy populations have been controversial. Although some studies have suggested no significant differences between the two[31,32]. ComerieSmith
et al[33] reported that even asymptomatic HIVpositive patients had increased colony counts of bacterial flora in the lids. Candida albicans, Candida parapsilosis, Staphylococcus aureus, Pseudomonas aeruginosa, Capnocytophaga, alphahemolytic streptococci, and Acanthamoeba have been isolated from infected corneas in patients with AIDS[34]. An adult AIDS patient with gonococcal infection developed keratoconjunctivitis. Preexisting keratoconjunctivitis sicca and viral keratitis, microvascular abnormalities, which present epithelial leakage giving rise to bacterial entry, and crack cocaine usage, are the risk factors for bacterial ocular infection in HIV/AIDS patients. Since systemic antibiotics are ineffective to ocular flora in HIVinfected patients[31], aggressive medication or surgical intervention should be considered once the diagnosis is made.
MICROVASULOPATHY
Microvasculopathy, also known as AIDS retinopathy, is the most common ocular complication, and it can affect 40%60% of AIDS patients and HAART has greatly decrease its incidence[35]. Its frequency increases according to the stage of HIV progression. Notably, a decreasing CD4+ count correlates with the occurrence of HIVrelated retinopathy, especially in those with CD4+ counts less than 200 cells/mm[3,36]. It is a noninfectious microvascular disorder characterized by cottonwool spots, microaneurysms, retinal hemorrhages, telangiectatic vascular changes, and the presence of capillary nonperfusion[1]. Although commonly found in the retina, microvasculopathy may present in conjunctiva and optic disk. Because of the isolation of HIV from human retina and the detection of its antigen in retinal endothelial cells, it is believed that HIV infection of endothelial cells may contribute to this ocular abnormity. Microvascular abnormalities in those with HIVassociated retinopathy include loss and degeneration of pericytes, swollen endothelial cells, thickened basement membranes, shrunken capillary lumina in retinal vessels and tubuloreticular structures, all of which are found in almost all HIVpositive patients[36,37].
Reduced leukocyte density in macular capillaries, which may lead to retinal hypoxia, and increased polymorphonuclear leukocyte rigidity, which can cause microvascular damage by releasing proteases, toxic oxygen radicals, as well as influence microvascular blood flow, are commonly found in HIVpositive patients[36,38]. Even without retinopathy or optic nerve disease, obvious thinning of the retinal nerve fiber layer is found in HIVpositive patients[39,40]. Other factors, such as damage from immune complexes and hemorrhagic abnormalities, can also contribute to the vascular alterations. Both the structural proteins and the regulatory proteins of HIV itself play a role in the viral ocular infection. It has been reported that HIV gp120 can activate apoptosis in endothelial cells and change the function barrier of the microvascular endothelial cell monolayer by increasing vasopermeability[41].
Moreover, HIV Tat protein, a transcriptional activator of viral gene expression produced early after infection, exerts both proliferative and apoptotic effects on endothelial cells[41,42]. It has been shown in vitro to induce changes of the tight junction proteins in the retinal pigment epithelium (RPE), which is responsible for altering the bloodretinal barrier and subsequent HIV trafficking into the eyes[43,44]. Microvasculopathy is often asymptomatic and no treatment is involved in most cases[36,45]. However, it may be the initial cause of other ocular complications in HIVpositive patients, such as CMV infection, retinal and optic nerve damage and various vision abnormalities, including abnormal color vision, reduced contrast sensitivity, and visual field abnormalities[46]. The severity of vascular damage correlates well with the multiple opportunistic infections in AIDS patients[47].
NEOPLASM
Cancer in individuals living with HIV/AIDS is a common source of morbidity and mortality. Although ocular malignancies are rare, they occur in the late stage of AIDS. The etiologies, primary sites, and treatments of three common ocular tumors in HIV/AIDS patients were summarized in Table 4.
Ocular Surface Squamous Neoplasia Squamous cell carcinoma which is characterized as a lowgrade malignancy is the third most common AIDSrelated neoplasm[48]. When the eyes are involved in the disease, the most common sites are the anterior parts, especially the conjunctiva and the eyelids. The pathogenesis of ocular surface squamous neoplasi (OSSN) is not well understood. However, exposure to ultraviolet radiation, genetic susceptibility and infection by HIV and HPV are the recognized factors that contribute to the high risk of developing OSSN[49]. Squamous cell conjunctival carcinoma is much more commonly seen in tropical, subtropical and poorer areas than in developed countries such as Europe and the United States[50]. It is reported that HIV positive patients have as high as 13fold increased risk of developing OSSN than the normal group[51] and the occurrence rate of OSSN reach 7.8% in AIDS patients[52]. HIV patients from subSaharan Africa seem to be at increased risk of OSSN. OSSN is more aggressive in HIV patients. In some cases, OSSN can be the initial clinical manifestation of HIV infection[53]. Although the DNA of HPV, predominantly type 16, has been found in ocular surface squamous neoplasias, the roles of HPV in the pathogenesis of OSSN have been controversial[50]. Diagnosis of OSSN can easily be mistaken with conjunctivitis and Pterygium[54] and the common treatment is the surgical excision of the lesion. As a result of the high recurrence after the surgery, cryotherapy, radiation and chemotherapy are also suggested and periodic followup examination is needed[55]. When the disease progresses and intraocular invasion occurs, such as perineural invasion, the disease may lead to death[56].
Kaposis Sarcoma Kaposis sarcoma (KS) is one of the most common and important AIDSrelated neoplasms and can be considered as an AIDSdefining illness[57]. Since human herpes virus8 (HHV8) has been identified in all four clinicalepidemiological forms of KS and since the viral load is correlated to the risk and severity of KS, HHV8 is considered to be the etiology of KS. However, only some HHV8positive populations develop KS. Therefore, HHV8 is necessary, but not sufficient, for the development of KS[58,59]. Other pathogens, such as CMV, HHV6, HHV7 and human papilloma viruses (HPV), may also be associated with the development of KS. Prior to the AIDS epidemic, KS was extremely rare. Now, however, KS is commonly seen, especially in AIDS patients. The incidence of KS in AIDS patients is about 20000 times higher than that found in the general population. The pathogenesis of AIDSKS may represent a series of events involving interaction of immunosuppression, altered expression and response to cytokines, and the cotransactivation between HIV and HHV8[60,61]. HIV1 Tat protein has been shown to be a potent mitogen for human KSderived cell lines and facilitates the development of KS by protecting KS cells from apoptosis[62]. Before the era of HAART, approximately 20% of HIVpositive patients suffer asymptomatic KS of the eyelids or conjunctiva[63]. Ocular involvement accounts for 1020% of AIDSrelated KS cases even in the era of highly active antiretroviral therapy (HAART)[6466], mostly the anterior parts, such as eyelids, the bulbar, tarsal, and forniceal conjunctiva, the plica semilunaris, the caruncle, the lacrimal sac, and rarely the orbit and lacrimal gland[67,68]. Eyelid and conjunctiva are the most commonly affected sites, and HHV8 has been detected in KS of the eyelid and conjunctiva in an AIDS patient[69]. Ocular KS usually presents as a red mass and can easily be mistaken for hemorrhage[65]. No specific therapy is available for ocular KS, although HAART may be used for treatment of AIDSassociated KS. If the lesion is painful or causes functional disruption, cryotherapy, surgical excision, radiation and/or chemotherapy are suggested[66,70].
Lymphoma NonHodgkins lymphoma (NHL), a kind of malignancy of Bcell origin associated with EpsteinBarr virus (EBV) infection[71], is the second most common malignant disorder associated with AIDS[72]. Ocular NHL may arise from the central nervous system (CNS) and/or retina, termed as primary CNS lymphoma, or may appear as intraocular metastasis from systemic lymphomas via blood circulation to the uvea, which is termed primary intraocular lymphoma. NHL can present in posterior and anterior parts, but are mostly confined to the conjunctiva and eyelid. Coexistence of intraocular and orbital nonHodgkins lymphoma has been reported in AIDS patients. Massive necrosis involving the retina, choroid, and optic nerve, as well as several solid retinal pigment epithelial detachments and retinal vasculitis, could be observed[73]. The pathogenesis of AIDSrelated lymphoma is unknown. Some studies, however, have found that HIV1 Vpu and Tat protein can support the expansion of malignant B cells[74]. HIV has no direct oncogenic effect since HIV sequences have never been detected within the neoplastic lymphoid cells[75]. Lack of immunosurveillance and viral infection, other than HIV, may be key factors contributing to lymphomagenesis[76]. No specific treatment, but only the traditional radiation and chemotherapy are recommended.
NEUROOPHTHALMIC ABNORMALITIES
Histological studies have shown that up to 75%90% of HIV/AIDS patients have brain damage, including the optic nerve. Sixty percent of HIV patients with neurological symptoms have some form of neuroophthalmological deficit. Many factors, such as CNS infection by HIV alone or with other coinfecting pathogens, neoplasms, inflammatory processes etc. may contribute to the neuroocular manifestation in HIV/AIDS patients[77]. Optic neuropathy, papilledema, and cranial nerve palsies are the most commonly found cases. Optic neuropathies can be caused by viral, bacterial or fungal infections, commonly found are CMV and Cryptococcus neoformans invasion. Cryptococcal meningitis can also be the cause of papilledema. Along with the HIV ongoing replication, neurotoxins are produced to cause apoptosis in specific neural tissues that lead to axonal loss, neuronal damage, and finally, neuroophthalmologic abnormalities.
CAUTIONS OF HAART
Drug resistance, adverse side effects and drugdrug interaction have been universal problems with the application of HAART for HIV infected patients. Clinicians should be particularly aware of the side effects of HAART related to the eyes. For instance, the toxicity of nucleoside reverse transcriptase inhibitor therapy in terms of the potential inhibition of host mitochrondrial DNA polymerase is well known. There are reports that longterm use of zidovudine may account for the late complication of Lebers hereditary optic neuropathy, which is caused by an induced mutation in the mitochondrial DNA[78,79]. So, HIVinfected patients with a family history of Lebers hereditary optic neuropathy should be warned of this ocular disorder. Zidovudine and protease inhibitors (PIs) used alone can induce endothelial cell proliferation, causing a dysregulation of angiogenesis, which makes HIVpositive patients more prone to hemangiomas such as KS[41,80]. The continued use of PIs may also increase the incidence of herpes zoster in AIDS patients. Application of nevirapine can lead to StevensJohnson syndromeinduced dry eye[81].
Surprisingly, combination of HAART and antituberculosis therapy in AIDS patients may actually weaken ocular condition[82]. On the other hand, the discontinuation of HAART can lead to ocular opportunistic infections, such as cryptococcal meningitis, which may result in choroiditis[27]. Immune recovery uveitis may occur in HIV/AIDS patients with CMV retinitis who have experienced immune recovery due to HAART[5]. Therefore, individualized treatment and regular monitoring should always be undertaken in HIV/AIDS patients.
OPHTHALMIC FINDINGS IN PEDIATRIC HIV INFECTIONS
The introduction of HAART seems to have a more significant impact on the nature of ocular manifestation in pediatric HIV infection in developed countries than that in the poor countries. A study in Milan, Italy, showed that there was 7.7% cases of ocular complication in the preHAART era while no case was found since the introduction of HAART in HIVinfected children[83]. However, similar incidence rate of ocular complication was found in African HIVinfected children regardless of HAART(Table 5).
CMV retinitis occur far less frequently in HIVpositive children than in adults and it is diagnosed predominantly in patients with CD4 cells counts below 20cell/μL, owing to the immature immune status and less frequent exposure to CMV in pediatric HIVinfected patients. The most significant ocular finding is the high incidence of perivasculitis and/or sheathing of retinal vessels in Africa and anterior uveitis in India. Nutritional status is probably the most important factor that contributes to the high prevalence of ocular involvement in HIVpositive children in developing countries.
CONCLUSION
HIV/AIDSrelated ophthalmologic problems will remain an important issue for the coming decades. Nowadays, the study of ocular complications in HIV/AIDS patients mainly focuses on the clinical features and prevalence, but seldom the potential mechanism of the pathogenesis, perhaps due to the lack of proper animal system models. In any case, it is only when we clearly understand what happens during the ocular/HIV pathogenic process that we can find successful therapeutic strategies. This will require the longterm commitment of both virologists and ophthalmologists.
【参考文献】
1 Biswas J, Fogla R, Gopal L, Narayana KM, Banker AS, Kumarasamy N, Madhavan HN. Current approaches to diagnosis and management of ocular lesions in human immunodeficiency virus positive patients. Indian J Ophthalmol 2002;50:8396
2 Shah SU, Kerkar SP, Pazare AR. Evaluation of ocular manifestations and blindness in HIV/AIDS patients on HAART in a tertiary care hospital in western India. Br J Ophthalmol 2009;93 (1):8890
3 Biswas J, Madhavan HN, George AE, Kumarasamy N, Solomon S. Ocular lesions associated with HIV infection in India: a series of 100 consecutive patients evaluated at a referral center. Am J Ophthalmol 2000;129:915
4 Rodrigues ML, Rodrigues ML, Figueiredo JF, de Freitas JA. Ocular problems in Brazilian patients with AIDS before and in highly active antiretroviral therapy (HAART) era. Braz J Infect Dis 2007;11:199202
5 Jabs DA, Van Natta ML, Kempen JH, Reed PP, Lim JI, Murphy RL, Hubbard LD. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2002;133:4861
6 Holland GN, Vaudaux JD, Jeng SM, Yu F, Goldenberg DT, Folz IC, Cumberland WG, McCannel CA, Helm CJ, Hardy WD. Characteristics of untreated AIDSrelated cytomegalovirus retinitis. I. Findings before the era of highly active antiretroviral therapy (1988 to 1994). Am J Ophthalmol 2008;145:511
7 Cochereau I, MlikaCabanne N, Godinaud P, Niyongabo T, Poste B, Ngayiragije A, Dazza MC, Aubry P, Larouze B. AIDS related eye disease in Burundi, Africa. Br J Ophthalmol 1999;83(3):339342
8 Ng WT, Versace P. Ocular association of HIV infection in the era of highly active antiretroviral therapy and the global perspective. Clin Experiment Ophthalmol 2005;33:317329
9 Wiafe B. Herpes Zoster Ophthalmicus in HIV/AIDS. Community Eye Health 2003;16:3536
10 Nwosu NN. HIV/AIDS in ophthalmic patients: The Guinness Eye Centre Onitsha experience. Niger Postgrad Med J 2008;15:2427
11 Umeh RE. Herpes zoster ophthalmicus and HIV infection in Nigeria.
Int J STD AIDS 1998;9:476479
12 Owoeye JF, AdemolaPopoola DS. Herpes zoster infection and HIV seropositivity among eye patientsUniversity of Ilorin Teaching Hospital experience. West Afr J Med 2003;22:136138
13 Gariano RF, Berreen JP, Cooney EL. Progressive outer retinal necrosis and acute retinal necrosis in fellow eyes of a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 2001;132 (3):421423
14 Yin PD, Kurup SK, Fischer SH, Rhee HH, Byrnes GA, LevyClarke GA, Buggage RR, Nussenblatt RB, Mican JM, Wright ME. Progressive outer retinal necrosis in the era of highly active antiretroviral therapy: successful management with intravitreal injections and monitoring with quantitative PCR. J Clin Virol 2007;38:254259
15 Ikoona E, Kalyesubula I, Kawuma M. Ocular manifestations in paediatric HIV/AIDS patients in Mulago Hospital, Uganda. Afr Health
Sci 2003;3(2):8386
16 Merisier H, Cochereau I, HoangXuan T, Toublanc M, Ruggeri C. Multiple molluscum contagiosum lesions of the limbus in a patient with HIV infection. Br J Ophthalmol 1995;79:393394
17 Schulz D, Sarra GM, Koerner UB, Garweg JG. Evolution of HIV1related conjunctival molluscum contagiosum under HAART: report of a bilaterally manifesting case and literature review. Graefes Arch Clin Exp Ophthalmol 2004;242:951955
18 Koopman RJ,van Merrienboer FC,Vreden SG,Dolmans WM.Molluscum contagiosum;a marker for advanced HIV infection. Br J Dermatol 1992;126(5):528529
19 PerezBlazquez E, Villafruela I, Madero S. Eyelid molluscum contagiosum in patients with human immunodeficiency virus infection. Orbit 1999;18(2):7581
20 Leahey AB, Shane JJ, Listhaus A, Trachtman M. Molluscum contagiosum eyelid lesions as the initial manifestation of acquired immunodeficiency syndrome. Am J Ophthalmol 1997;124(2):240241
21 Schornack MM, Siemsen DW, Bradley EA, Salomao DR, Lee HB. Ocular manifestations of molluscum contagiosum. Clin Exp Optom 2006;89(6):390393
22 Bardenstein DS, Elmets C. Hyperfocal cryotherapy of multiple Molluscum contagiosum lesions in patients with the acquired immune deficiency syndrome. Ophthalmology 1995;102(7):10311034
23 Lee MW, Fong KS, Hsu LY, Lim WK. Optic nerve toxoplasmosis and orbital inflammation as initial presentation of AIDS. Graefes Arch
Clin Exp Ophthalmol 2006;244:15421544
24 CochereauMassin I,LeHoang P,LautierFrau M,Zerdoun E,Zazoun L,Robinet M,Marcel P,Girard B,Katlama C,Leport C.Ocular toxoplasmosis in human immunodeficiency virusinfected patients. Am J Ophthalmol 1992;114:130135
25 Babu RB, Sudharshan S, Kumarasamy N, Therese L, Biswas J. Ocular tuberculosis in acquired immunodeficiency syndrome. Am J Ophthalmol 2006;142:413418
26 Welton TH, Townsend JC, Bright DC, Anderson SF, Nguyen AT, Ilsen PF. Presumed ocular tuberculosis in an AIDS patient. J Am Optom
Assoc 1996;67(6):350357
27 Chronister CL. Discontinuation of highly active antiretroviral therapy leads to cryptococcal meningitis/choroiditis in an AIDS patient. Optometry 2006;77:438445
28 Nkomazana O, Tshitswana D. Ocular complications of HIV infection in subSahara Africa. Curr HIV /AIDS Rep 2008;5:120125
29 Andreola C, Ribeiro MP, de Carli CR, Gouvea AL, Curi AL. Multifocal choroiditis in disseminated Cryptococcus neoformans infection. Am J Ophthalmol 2006;142:346348
30 Jong AY, Wu CH, Jiang S, Feng L, Chen HM, Huang SH. HIV1 gp41 ectodomain enhances Cryptococcus neoformans binding to HBMEC.
Biochem Biophys Res Commun 2007;356:899905
31 Gritz DC, Scott TJ, Sedo SF, Cevallos AV, Margolis TP, Whitcher JP. Ocular flora of patients with AIDS compared with those of HIVnegative patients. Cornea 1997;16:400405
32 Campos MS, Campos e Silva Lde, Rehder JR, Lee MB, OBrien T, McDonnell PJ. Anaerobic flora of the conjunctival sac in patients with AIDS and with anophthalmia compared with normal eyes. Acta Ophthalmol(Copenh) 1994;72(2):241245
33 ComerieSmith SE, Nunez J, Hosmer M, Farris RL. Tear lactoferrin levels and ocular bacterial flora in HIV positive patients. Adv Exp Med
Biol 1994;350:339344
34 Tandon R, Vajpayee RB, Gupta V, Vajpayee M, Satpathy G, Dada T.Polymicrobial keratitis in an HIVpositive patient. Indian J Ophthalmol 2003;51(1):8788
35 Kozak I, Sample PA, Hao J, Freeman WR, Weinreb RN, Lee TW, Goldbaum MH. Machine learning classifiers detect subtle field defects in eyes of HIV individuals. Trans Am Ophthalmol Soc 2007;105:111118
36 DejacoRuhswurm I, Kiss B, Rainer G, Krepler K, Wedrich A, Dallinger S, Rieger A, Schmetterer L. Ocular blood flow in patients infected with human immunodeficiency virus. Am J Ophthalmol 2001;132:720726
37 Maturi RK, Font RL. Ultrastructural features and prevalence of tubuloreticular structures in the ocular vasculature of patients with AIDS: a study of 23 cases. Br J Ophthalmol 1996;80:252255
38 Tufail A, Holland GN, Fisher TC, Cumberland WG, Meiselman HJ. Increased polymorphonuclear leucocyte rigidity in HIV infected individuals. Br J Ophthalmol 2000;84:727731
39 Plummer DJ, Bartsch DU, Azen SP, Max S, Sadun AA, Freeman WR. Retinal nerve fiber layer evaluation in human immunodeficiency viruspositive patients. Am J Ophthalmol 2001;131:216222
40 Besada E, Shechtman D, Black G, Hardigan PC. Laser scanning confocal ophthalmoscopy and polarimetry of human immunodeficiency virus patients without retinopathy, under antiretroviral therapy. Optom Vis Sci 2007;84:189196
41 Bussolino F, Mitola S, Serini G, Barillari G, Ensoli B. Interactions between endothelial cells and HIV1. Int J Biochem Cell Biol 2001;33(4):371390
42 Wu RF, Ma Z, Myers DP, Terada LS. HIV1 Tat activates dual Nox pathways leading to independent activation of ERK and JNK MAP kinases. J Biol Chem 2007;282(52):3741237419
43 Matzen K, Dirkx AE, oude Egbrink MG, Speth C, Gotte M, Ascherl G, Grimm T, Griffioen AW, Sturzl M. HIV1 Tat increases the adhesion of monocytes and Tcells to the endothelium in vitro and in vitro: implications for AIDSassociated vasculopathy. Virus Res 2004;104(2):145155
44 Bai L, Zhang Z, Zhang H, Li X, Yu Q, Lin H, Yang W. HIV1 Tat protein alter the tight junction integrity and function of retinal pigment epithelium: an in vitro study. BMC Infect Dis 2008;8:77
45 Banker AS. Posterior segment manifestations of human immunodeficiency virus/acquired immune deficiency syndrome. Indian J Ophthalmol 2008;56(5):377383
46 Holland GN. AIDS and ophthalmology: the first quarter century. Am J Ophthalmol 2008;145:397408
47 Schmidt D. The mystery of cottonwool spots a review of recent and historical descriptions. Eur J Med Res 2008;13(6):231236
48 De Silva DJ, Tumuluri K, Joshi N. Conjunctival squamous cell carcinoma: atypical presentation of HIV. Clin Experiment Ophthalmol 2005;33(4):419420
49 Newton R. A review of the aetiology of squamous cell carcinoma of the conjunctiva. Br J Cancer 1996;74(10):15111513
50 Tornesello ML, Duraturo ML, Waddell KM, Biryahwaho B, Downing R, Balinandi S, Lucas SB, Buonaguro L, Buonaguro FM. Evaluating the role of human papillomaviruses in conjunctival neoplasia. Br J Cancer 2006;94(3):446449
51 GuechOngey M, Engels EA, Goedert JJ, Biggar RJ, Mbulaiteye SM. Elevated risk for squamous cell carcinoma of the conjunctiva among adults with AIDS in the United States. Int J Cancer 2008;122(11):25902593
52 Chisi SK, Kollmann MK, Karimurio J. Conjunctival squamous cell carcinoma in patients with human immunodeficiency virus infection seen at two hospitals in Kenya. East Afr Med J 2006;83(5):267270
53 Osahon AI, Onunu AN. Ocular disorders in patients infected with the human immunodeficiency virus at the University of Benin Teaching Hospital, Benin City, Nigeria. Niger J Clin Pract 2007;10(4):283286
54 Zhang Z, Li B, Shi J, Xu X, Li L, Gao F. Intraocular extension of conjunctival squamous cell carcinoma. Ophthalmologica 2007;221(3):200203
55 Gichuhi S, Irlam JJ. Interventions for squamous cell carcinoma of the conjunctiva in HIVinfected individuals. Cochrane Database Syst Rev 2007(2):CD005643
56 Kaines A, Davis G, Selva D, Leibovitch I, Dodd T, Malhotra R. Conjunctival squamous cell carcinoma with perineural invasion resulting in death. Ophthalmic Surg Lasers Imaging 2005;36(3):249251
57 Curtis TH, Durairaj VD. Conjunctival Kaposi sarcoma as the initial presentation of human immunodeficiency virus infection. Ophthal Plast
Reconstr Surg 2005;21:314315
58 Feller L, Lemmer J. Insights into pathogenic events of HIVassociated Kaposi sarcoma and immune reconstitution syndrome related Kaposi sarcoma. Infect Agent Cancer 2008; 3:1
59 Sarwar N, Stebbing J, Bower M. Translational review of AIDSrelated Kaposis sarcoma. Update on Cancer Therapeutics 2007;2:5360
60 Tirelli U, Bernardi D, Spina M, Vaccher E. AIDSrelated tumors: integrating antiviral and anticancer therapy. Crit Rev Oncol Hematol 2002;41(3):299315
61 Aversa SM, Cattelan AM, Salvagno L, Crivellari G, Banna G, Trevenzoli M, ChiarionSileni V, Monfardini S. Treatments of AIDSrelated Kaposis sarcoma. Crit Rev Oncol Hematol 2005;53(3):253265
62 Deregibus MC, Cantaluppi V, Doublier S, Brizzi MF, Deambrosis I, Albini A, Camussi G. HIV1Tat protein activates phosphatidylinositol 3kinase/ AKTdependent survival pathways in Kaposis sarcoma cells. J Biol Chem 2002;277(28):2519525202
63 Dugel PU, Gill PS, Frangieh GT, Rao NA. Ocular adnexal Kaposis sarcoma in acquired immunodeficiency syndrome. Am J Ophthalmol 1990;110(5):500503
64 Pantanowitz L, Dezube BJ. Kaposi sarcoma in unusual locations. BMC Cancer 2008;8:190
65 Kagu MB, Nggada HA, Garandawa HI, Askira BH, Durosinmi MA. AIDSassociated Kaposis sarcoma in Northeastern Nigeria. Singapore
Med J 2006;47(12):10691074
66 Biswas J, Sudharshan S. Anterior segment manifestations of human immunodeficiency virus/acquired immune deficiency syndrome. Indian J
Ophthalmol 2008;56(5):363375
67 Scheschonka A, Mosch M, Krieglsteiner S, Turowski B, Zanella FE. Pre and posttreatment MR imaging in AIDSrelated Kaposi sarcoma of the conjunctiva and lacrimal gland. AJNR Am J Neuroradiol 2003;24(7):13271329
68 Jeng BH, Holland GN, Lowder CY, Deegan WF, III, Raizman MB, Meisler DM. Anterior segment and external ocular disorders associated with human immunodeficiency virus disease. Surv Ophthalmol 2007;52:329368
69 Minoda H, Usui N, Sata T, Katano H, Serizawa H, Okada S. Human herpesvirus8 in Kaposis sarcoma of the conjunctiva in a patient with AIDS. Jpn J Ophthalmol 2006;50(1):711
70 Brun SC, Jakobiec FA. Kaposis sarcoma of the ocular adnexa. Int Ophthalmol Clin 1997;37:2538
71 Bonnet F, Jouvencel AC, Parrens M, Leon MJ, Cotto E, Garrigue I, Morlat P, Beylot J, Fleury H, Lafon ME. A longitudinal and prospective study of EpsteinBarr virus load in AIDSrelated nonHodgkin lymphoma. J Clin Virol 2006;36(4):258263
72 Peterson OD, Kirwan OD. A rare ocular manifestation of nonHodgkins lymphoma. Clinical Eye and Vision Care 1999;11:199206
73 Matzkin DC, Slamovits TL, Rosenbaum PS. Simultaneous intraocular and orbital nonHodgkin lymphoma in the acquired immune deficiency syndrome. Ophthalmology 1994;101(5):850855
74 Smith JR, Henderson WW, Rosenbaum JT, Neuwelt EA, Moses AV. Cultured human endothelial cells expressing HIV1 Vpu and Tat support the expansion of malignant B cells from primary central nervous system lymphoma. Br J Ophthalmol 2008;92:297299
75 Dal Maso L, Franceschi S. Epidemiology of nonHodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS. Lancet
Oncol 2003;4(2):110119
76 Pietersma F, Piriou E, van Baarle D. Immune surveillance of EBVinfected B cells and the development of nonHodgkin lymphomas in immunocompromised patients. Leuk Lymphoma 2008;49(6):10281041
77 Mwanza JC, Nyamabo LK, Tylleskar T, Plant GT. Neuroophthalmological disorders in HIV infected subjects with neurological manifestations. Br J Ophthalmol 2004;88(11):14551459
78 Mackey DA, Fingert JH, Luzhansky JZ, McCluskey PJ, Howell N, Hall AJ, Pierce AB, Hoy JF. Lebers hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus. Eye 2003;17:312317
79 Shaikh S, Ta C, Basham AA, Mansour S. Leber hereditary optic neuropathy associated with antiretroviral therapy for human immunodeficiency virus infection. Am J Ophthalmol 2001;131:143145
80 Di Simone N, De Santis M, Tamburrini E, Di Nicuolo F, Lucia MB, Riccardi P, DIppolito S, Cauda R, Caruso A. Effects of antiretroviral therapy on tubelike network formation of human endothelial cells. Biol Pharm Bull 2007;30(5):982984
81 Jain V, Shome D, Natarajan S. Nevirapineinduced StevensJohnson syndrome in an HIV patient. Cornea 2008;27(3):366367
82 Biswas J, Sudharshan S, Babu RB. Ocular lesions in AIDS: Indian scenario. Am J Ophthalmol 2008;146(2):331
83 Esposito S, Porta A, Bojanin J, Gualtieri L, Cesati L, Vismara E, Principi N. Effect of highly active antiretroviral therapy (HAART) on the natural history of ocular manifestations in HIVinfected children. Eye 2006;20:595597
84 Ndoye NB, Sow PS, Ba EA, Ndiaye MR, Wade A, CollSeck AM. Ocular manifestations of AIDS in Dakar. Dakar Med 1993;38:97100
85 Nagata Y, Fujino Y, Matsumoto S, Nishi M, Ono A, Mochizuki M, Oka S, Kimura S, Shimada K. Ocular manifestations in Japanese patients with human immunodeficiency virus infection. Jpn J Ophthalmol 1993;37:275281
86 Chiou SH, Liu CY, Hsu WM, Chan YJ, Chou CK, Chung YM, Liu JH, Liu WT, Chen SC, Wong WW. Ophthalmic findings in patients with acquired immunodeficiency syndrome. J Microbiol Immunol Infect 2000;33:4548
87 Lim SA, Heng WJ, Lim TH, Leo YS, Wong SY. Ophthalmic manifestations in human immunodeficiency virus infection in Singapore. Ann Acad Med Singapore 1997;26:575580
88 Muccioli C, Belfort JR, Lottenberg C, Lima J, Santos P, Kim M, de Abreu MT, Neves R. Ophthalmological manifestations in AIDS: evaluation of 445 patients in one year. Rev Assoc Med Bras 1994;40(3):155158
89 Matos KT, Santos MC, Muccioli C. Ocular manifestations in HIV infected patients attending the department of ophthalmology of Universidade Federal de Sao Paulo. Rev Assoc Med Bras 1999;45:323326
90 Mesaric B, Lisic M, Kniewald T, Ugrinovic N, Begovac J. Ocular manifestations in patients with human immunodeficiency virus infection before and after the introduction of highly active antiretroviral therapy. Lijec Vjesn 2005;127:123128
91 Adepoju FG, Olawumi HO, Adekoya BJ. HIV seropositivity and related eye diseases in Uith, Ilorin. Niger Postgrad Med J 2007;14:163165
92 Kahraman G, Krepler K, Franz C, Ries E, Maar N, Wedrich A, Rieger A, DejacoRuhswurm I. Seven years of HAART impact on ophthalmic management of HIVinfected patients. Ocul Immunol Inflamm 2005;13:213218
93 Miyamoto C, Yashiro S, Nagata Y, Nagataki S. Ocular complications in patients infected with human immunodeficiency virus seen at the Acquired Immunodeficiency Syndrome Clinical Center. Nippon Ganka Gakkai Zasshi 2001;105:483487
94 Ausayakhun S, Watananikorn S, Ittipunkul N, Chaidaroon W, Patikulsila P, Patikulsila D. Epidemiology of the ocular complications of HIV infection in Chiang Mai. J Med Assoc Thai 2003;86:399406
95 Gharai S, Venkatesh P, Garg S, Sharma SK, Vohra R. Ophthalmic manifestations of HIV infections in India in the era of HAART: analysis of 100 consecutive patients evaluated at a tertiary eye care center in India. Ophthalmic Epidemiol 2008;15(4):264271
96 Biswas PN, Saha B, Ghosh S, Mallik S, Nandi K, Niyogi DK, Bhaduri G. Ophthalmic manifestations in people living with HIV attending a tertiary care centre of Eastern India. J Indian Med Assoc 2008;106(5):292294
97 Inoue T, Hayashi K, Omoto T, Kosaki R, Higaki S, Shimomura Y. Corneal infiltration and CMV retinitis in a patient with AIDS. Cornea 1998;17:441442
98 Cheng L,Rao NA,Keefe KS,Avila CP Jr.,MacDonald JC,Freeman WR.Cytomegalovirus iritis. Ophthalmic Surg Lasers 1998;29:930932
99 Wilhelmus KR, Font RL, Lehmann RP, Cernoch PL. Cytomegalovirus keratitis in acquired immunodeficiency syndrome. Arch Ophthalmol 1996;114:869872
100 Patel SS, Rutzen AR, Marx JL, Thach AB, Chong LP, Rao NA. Cytomegalovirus papillitis in patients with acquired immune deficiency syndrome. Visual prognosis of patients treated with ganciclovir and/or foscarnet. Ophthalmology 1996;103:14761482
101 Park KH,Bang JH,Park WB,Kim HB,Kim NJ,Ahn JK,Chang KH,Oh MD,Choe KW.Retrobulbar Optic Neuritis and Meningoencephalitis Following Progressive Outer Retinal Necrosis due to CMV in a Patient with AIDS. Infection 2008:36(5):475479
102 FrancoParedes C, Bellehemeur T, Merchant A, Sanghi P, DiazGranados C, Rimland D. Aseptic meningitis and optic neuritis preceding varicellazoster progressive outer retinal necrosis in a patient with AIDS. AIDS 2002;16(7):10451049
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