Since 1981, when the first case of acquired immunodeficiency syndrome (AIDS) was diagnosed, the number of cases of human immunodeficiency virus (HIV) infection has been continuously increasing around the world. Therefore, understanding HIV/AIDS as much as possible is the responsibility of every healthcare professional. In this journal review, we present the salient ocular manifestations of HIV/AIDS, and the effect of highly active antiretroviral therapy (HAART) on the pattern of presentation of HIV ocular disease.
Holland et al. (Ophthalmology 1983; 90:859-73) reported findings of ophthalmic and autopsy examinations of 30 patients of AIDS in the US. The anterior segment findings (n=8) included conjunctivitis and keratitis (n=4) and conjunctival Kaposi′s sarcoma (n=3).
Umeh et al. (Int J STD AIDS 1998; 9(8):476-9) reported herpes zoster ophthalmicus (HZO) in patients of AIDS. Ocular examination revealed impaired vision in the affected eye in all the patients; all had lid edema while five had ptosis (three partial and two complete). Variable degrees of conjunctival injection were observed in all patients while six of them had corneal anesthesia and keratitis. Uveal inflammation, present in all the patients, varied from mild to severe iridocyclitis. None had any associated abnormalities in the posterior segment.
Verma et al. (Int J STD AIDS 1999;10(4):268-74) studied case notes of all HIV-positive patients (n=172) presenting to them with symptoms of uveitis over a four-year period. Only 12 patients were identified to have symptomatic uveitis out of a total of 172 patients. They concluded that anterior uveitis is not very symptomatic in HIV-positive individuals.
Neves (Cornea 1996;15(5):446-50) described the clinical characteristics and course of peripheral ulcerative keratitis (PUK) secondary to herpes varicella-zoster virus in patients of AIDS. All the three patients had skin involvement, and two of them had bilateral keratouveitis. All were treated with high-dose oral acyclovir (4 g/day) with or without topical antiviral therapy. Two of the patients responded well to oral acyclovir, but one of them stopped the treatment, and bilateral progressive outer retinal necrosis and lethal encephalitis developed. The third patient had a recurrent episode of inflammation with PUK, extensive stromal scarring, and deep neovascularization.
Posterior segment manifestations
Chiou et al. (J Microbiol Immunol Infect. 2000;33(1):45-8) in their study examined and followed up the ophthalmic conditions of a total of 274 HIV-infected patients. The results showed that cotton-wool spots was the most common ocular finding in this series and cytomegalovirus (CMV) retinitis was the most commonly seen opportunistic infection.
Gariano et al. ( Am J Ophthalmol. 2001;132(3):421-3) reported an unusual occurrence of acute retinal necrosis and progressive outer retinal necrosis (PORN) in fellow eyes of a 37-year-old man with AIDS.
Cochereau et al. ( Br J Ophthalmol. 1999;83(3):339-42) evaluated 154 consecutive patients of AIDS for ocular involvement and detected 16 cases of microangiopathy, six cases with opalescence of the anterior chamber, five cases of retinal perivasculitis, two cases of HZO, two cases of viral retinitis, and one case having opalescence of the vitreous. They concluded that in Africa, the prevalence of ocular involvement in HIV infection is far lower than in Europe and the United States, possibly because of low survival rate.
Lim et al. ( Ann Acad Med Singapore 1997;26(5):575-80) retrospectively reviewed the spectrum of ophthalmic manifestations of HIV infection in 118 HIV-positive individuals in Singapore between May 1995 and October 1996. Eighteen patients (15.3%) had abnormalities associated with microvasculature. Forty-four patients (37.3%) had opportunistic infection involving the eye of which 37 were that of CMV retinitis. Seven patients (5.9%) had neuro-ophthalmic disorders. One patient presented with proptosis due to orbital lymphoma. Four patients (3.4%) had episcleritis and three patients (2.5%) had symptomatic dry eyes. The major cause of visual loss was ocular infections, with CMV retinitis being most prevalent.
Ye et al. (Zhonghua Yan Ke Za Zhi 2005;41(9):803-6) described the typical appearance of CMV retinitis in patients of AIDS. It is characterized by retinal vasculitis; dense, full-thickness, yellow- white lesions along vascular distribution, and hemorrhage on the retinal surface; granular with irregular border featured as ″cheese and ketchup retinitis″ was revealed in 12 eyes; the vitreous was mostly clear or light opaque. Late stage of the retinopathy was demonstrated in two eyes characterized as greyish atrophic retina, sclerotic and attenuated vessels, retinal pigment epithelial (RPE) atrophy, and optic atrophy. Retinal detachment was found in one eye.
Jabs et al. ( Ophthalmology1989; 96:1092-9 ) reported ocular complications of 200 AIDS patients. AIDS retinopathy was present in 66.5%; 64% had cotton-wool spots, and 12% had intraretinal hemorrhages. CMV retinitis was diagnosed in 28% of patients. Neuro-ophthalmic lesions were seen in 8% of all AIDS patients and were present in 33% of patients with cryptococcal meningitis.
Ruggli et al. ( Ophthalmology1997;104(11):1853-6) reported white placoid conjunctival lesions and choroidal lesions secondary to Pneumocystis carinii infection in their patients.
Sweeney et al. ( J Psychiatry Neurosci. 1991;16(5):247-5) observed that seropositive patients demonstrated disturbances in pursuit eye movements that were correlated with extent of immunosuppression. They noted that oculomotor disturbances are present in HIV-1 seropositive individuals before the manifestation of marked AIDS Dementia Complex. For this reason, and because more severe eye movement impairments have been observed in patients with AIDS, quantitative eye movement studies may provide a useful neurobehavioral procedure for characterizing and monitoring progression of CNS involvement associated with HIV-1 infection from early in its course.
Mansour (J Clin Neuroophthalmol 1990; 10:167-74) reviewed the neuro-ophthalmic findings in 177 patients with AIDS or AIDS-related complex. The findings included ocular motor nerve palsies (n=5), papilledema (n=2), CMV optic neuritis (n=2), cortical blindness (n=1), conjugate gaze palsy (n=1), and altitudinal visual field defect (n=1). These findings were attributed to central nervous system toxoplasmosis (n=4) or lymphoma (n=1), cryptococcal meningitis (n=2), systemic CMV infections (n=2), and herpes simplex encephalitis (n=1).
Woods and Caputo ( Optom Clin. 1996;5(3-4):113-52) in their review, reported neuro-ophthalmic problems, including optic neuropathies, motility disturbances, and visual field defects, in patients of AIDS.
Ormerod et al. ( Ophthalmology 1996;103(6):899-906) in their study evaluated 10 patients in whom ophthalmologic manifestations developed in the course of AIDS-associated progressive multifocal leukoencephalopathy (PML). Homonymous visual field defects were the presenting symptom in three patients (n=10) and detected in six patients overall. Occipital blindness developed in one patient. Cerebellar signs and brainstem nuclear and supranuclear palsies were also noted. They concluded that the development of progressive retrochiasmal visual field defects, supranuclear and nuclear cranial nerve palsies, or nystagmus ataxia in the relatively young patient should alert the ophthalmologist to the possibility of HIV-associated PML.
Corti et al. (Enferm Infecc Microbiol Clin. 2001;19(1):3-6) in their study of 6,552 patients with HIV infection detected ocular Kaposi′s sarcoma in 17 (0.25%) patients, predominantly in the male sex (88.23%). The lesions predominated in the eyelids, particularly in the lower lid.
Mansour et al. ( Ophthal Plast Reconstr Surg. 1993;9(4):273-9) reviewed the adnexal and orbital findings in a large population with HIV infection. Around 6% of the series had positive periocular findings; in 1%, these were the first manifestations of HIV infection. Orbital findings included lymphoma, cellulitis, Kaposi′s sarcoma, and nonspecific inflammation. Adnexal findings included Kaposi′s sarcoma, molluscum contagiosum, bacterial folliculitis, madarosis, psoriasis, basal cell carcinoma, and chalazion.
Biswas J (Indian J Ophthalmol. 1997;45(4):233-4) reported blepharitis and lid ulcer as initial ocular manifestation in AIDS patients.
Leahey et al. (Am J Ophthalmol. 1997;124(2):240-1) reported atypical and extensive eyelid molluscum contagiosum in AIDS patients.
Chisi et al. (East Afr Med J. 2006;83(5):267-70) evaluated 409 HIV-positive patients aged 25 to 53 years and detected conjunctival growths in 103 patients suggestive of conjuctival squamous cell carcinoma (CSCC). Thirty-two had histologically proven CSCC. They reported that the estimated prevalence of CSCC among HIV-positive patients was 7.8%.
Kestelyn et al. ( Ocul Immunol Inflamm. 2000;8(4):263-73) described the ocular manifestations of HIV/AIDS infection in an African pediatric population. The overall rate of ophthalmic involvement was 54%. The most common finding was a perivasculitis of the peripheral retinal vessels, observed in 38% of the patients. CMV infection of the retina was diagnosed in three patients. Isolated cotton-wool spots of the retina were not observed. Ophthalmic herpes zoster and conjunctival xerosis responding to vitamin A administration were each seen in two patients. One-third of a subset of children tested for lacrimal function had evidence of decreased tear secretion. They concluded that cotton-wool spots and CMV retinitis, the most common ocular manifestations of HIV/AIDS in adults, are much less prevalent in children. The high incidence of perivasculitis, not observed or only seen in a few cases in other series, suggests that this ocular sign is more prevalent in African children.
Girard et al. ( J Fr Ophtalmol. 1997;20(1):49-60) in their study divided the retinal manifestations into two groups: venous dilatation and perivasculitis, and retinal opportunistic infections. Ocular toxoplasmosis was the main finding. They also reported one case of herpetic keratitis. Adnexal complications were represented by conjunctivitis and molluscum contagiosum. They concluded that manifestations of HIV infection in children appear to be different from adults.
Iordanescu et al. (Oftalmologia 1993;37(4):308-14) examined 33 children with AIDS and revealed manifestations of the anterior segment and of ocular adnexa in 10 cases. In eight cases they noticed seborrheic dermatitis, exudative dermatitis, molluscum contagiosum, and papulous eruptions. In three cases there were herpetic infections; one of which had herpetic keratitis. One case had Burkitt′s lymphoma with palpebral exteriorization. The fundus examination revealed retinal microvasculopathies with aneurysmal dilatations and retinal hemorrhages in three cases. Two cases had bilateral papillary and papilloretinal edema. In eight cases there was partial optic atrophy and in one case they noticed tapetoretinal degeneration.
Dennehy et al. (Arch Ophthalmol. 1989;107(7):978-82) in their study reported that 20% of HIV-positive individuals had ocular findings, including two cases of CMV retinitis, one case of isolated retinal cotton-wool spots, one case of toxoplasma retinochoroiditis, and three cases of external infections of adnexal structures.
Ikoona et al. (Afr Health Sci.2003;3(2):83-6) studied ocular manifestations in pediatric HIV/AIDS patients in Mulago Hospital, Uganda and reported an overall rate of ophthalmic involvement to be 35%. The most common finding was a non-purulent conjunctivitis (12%), followed by perivasculitis of peripheral retinal vessels (12%) and molluscum contagiosum.
In India the first cases of HIV were diagnosed among sex workers in Chennai, Tamil Nadu by Simoes et al., in 1986 ( Indian J Med Res. 1987; 85:335-8).
Biswas et al. ( Ind J Ophthalmol 1995:43:69-72) reported the first two cases of ocular lesions in AIDS in India. Ocular lesions included subretinal yellow mass in the first case and CMV retinitis and cotton-wool spots in the second case.
Biswas et al. ( Am J Ophthalmol. 2000;129(1):9-15) documented the ocular disorders seen in the first 100 individuals known to be HIV-positive at a referral eye clinic in India between 1993 and 1998. Most of the patients (76%) were in the 20-40 years age group. Heterosexual exposure to commercial sex workers was the most common risk factor (70%) for HIV infection. CMV retinitis (17%) and HIV retinopathy (15%) were the most common ophthalmic lesions.
Babu et al. (Am J Ophthalmol. 2006;142(3):413-8) presented the findings of ocular tuberculosis (TB) that was detected in 15 (1.95%) out of 766 consecutive cases of HIV/AIDS. Nineteen eyes of 15 patients were affected. Four cases (26.66%) had bilateral presentation. Presentations of ocular TB included choroidal granulomas in 10 eyes (52.63%), subretinal abscess in seven eyes (36.84%), worsening to panophthalmitis in three eyes, conjunctival TB, and panophthalmitis each in one eye (5.26%). They concluded that ocular TB in AIDS is relatively rare and can occur even at CD4+ counts greater than 200 cells/µl.
Mehta and Gilada (Ocul Immunol Inflamm. 2005;13(1):87-9), however, reported that ocular TB was a common finding in their study. Retinal hemorrhages, cotton-wool spots, HZO, CMV retinitis, and disc edema were other non-tubercular AIDS-related lesions.
Fogla et al. (Eye 2000;14:246-7) reported a case of squamous cell carcinoma of the conjunctiva as the initial presenting sign in a patient of AIDS due to HIV Type 2.
Battu et al ( Indian J Ophthalmol 2000; 48:47-9) reported a case of papilloedema with peripapillary retinal hemorrhages in an AIDS patient with cryptococcal meningitis.
Biswas et al. ( Ocul Immunol Inflamm 2001; 9:125-30) reported a case of central retinal vein occlusion due to herpes zoster as the initial presenting sign in a patient with AIDS.
Karna et al. ( Indian J Ophthalmol 2001; 49:118-20) reported a case of multiple cranial nerve palsy (sixth (bilateral), ninth, tenth and twelfth nerve palsies) in an HIV-positive patient.
Biswas et al. ( Indian J Pediatr. 2000;67(10):721-4) in their study reported that the spectrum of ocular lesions in children with HIV infection is different from that seen in adults. Vertical transmission was the most common mode of infection (58.33%). Ocular lesions were found in 50% of patients. The most common ocular lesions were anterior uveitis and CMV retinits (33%) followed by retinal detachment (16.66%) and vitreous hemorrhage (16.66%).
Correlation with CD4
Kuppermann et al. ( Am J Ophthalmol 1993;115(5):575-82) performed a correlation between CD4+ counts and prevalence of CMV retinitis and HIV-related noninfectious retinal vasculopathy in patients with AIDS. In patients with CD4+ counts of 50 cells/mm3 or less, 30% had CMV retinitis, whereas in patients with CD4+ counts of 50 cells/mm3 or more, none was noted to have CMV retinitis. Further, 35% were noted to have HIV-related noninfectious retinal vasculopathy, with a trend toward increasing prevalence associated with declining CD4+ count. In patients with CD4+ counts of 50 cells/mm3 or less, 45% had HIV-related noninfectious retinal vasculopathy, whereas 16% patients with CD4+ counts of 50 cells/mm3 or more were noted to have these changes. They concluded that CMV retinitis and HIV-related noninfectious retinal vasculopathy are late manifestations of AIDS, with an increased risk in patients with low CD4+ counts.
Pre-HAART and Post-HAART Era: A Comparative Evaluation
Holland et al. (Am J Ophthalmol. 2008;145(3):397-408) observed that the introduction of HAART has markedly reduced the incidence of CMV retinitis, but has not eliminated new cases altogether. Current issues of importance include choice of initial anti-CMV drugs; time at which anti-CMV drug treatment is discontinued in patients who achieve immune recovery; strategies for monitoring patients at risk for disease reactivation; and management of complications (retinal detachment, immune recovery uveitis).
Nasoodi et al. (Int J STD AIDS. 2008;19(1):4-11) also observed that the advent of HAART has reduced the incidence of ocular complications of HIV. In the face of emerging immune recovery, conditions such as immune recovery uveitis (IRU) could affect eyes with history of opportunistic disease with a potential to cause vision loss. Hence, differentiation of the inflammatory process from infective causes is essential.
Accorinti et al. (Eur J Ophthalmol. 2006;16(5):728-32) also observed that in the post-HAART era, HIV-related retinal microangiopathy and opportunistic retinal infections (CMV retinitis and toxoplasmic retinochoroiditis) were significantly lower. However, there was a statistically significant increase in the frequency of chalazion (p<0.0001), diabetic and hypertensive retinopathy (p<0.0001), cataract, glaucoma (p< 0.0001), and uveitis (p=0.026).
Kahraman et al. (Ocul Immunol Inflamm.2005;13(2-3):213-8) in their study reported 10.8% of the patients with CMV retinitis, most of whom had CMV retinitis before receiving HAART. Four patients developed immune-recovery uveitis.
Mesaric et al. (Lijec Vjesn. 2005;127(5-6):123-8) divided patients with confirmed HIV-1 infection into two groups: period before HAART (1995-1997, n=50) and period after HAART (1998-2000, n=47). In total, 208 ophthalmic abnormalities were recorded, 132 (63.5%) in the first and 76 (36.5%) in the second period. Vascular changes were most frequently diagnosed (113/208 or 54.3% cases) of which cotton-wool exudates were seen in 55 and microaneurysms in 54 cases. CMV retinitis was most commonly diagnosed among infectious ocular complications (altogether 39 episodes). Changes in the anterior segment were observed in 11/208 (5.3%) cases, while neuro- ophthalmic manifestations were seen in 39/208 patients (18.7%). The incidence of CMV retinitis episodes in the pre-HAART era was 57.2 per 100 years of follow-up, and 7.6 per 100 years of follow-up in the HAART era. The visual acuity in patients from the HAART era was significantly more frequently preserved.
Esposito et al. (Eye. 2006;20(5):595-7) studied the effect of HAART on the natural history of ocular manifestations in HIV-infected children. The cohort consisted of 117 HIV-infected children. A total of nine cases of ocular involvement (7.7%) were diagnosed between 1983 and 1994, before the introduction of HAART. No case of ocular involvement was observed after the introduction of HAART (p=0.011).
DeGrezia and Robinson (J Assoc Nurses AIDS Care. 2001;12(3):22-32) also reported that the introduction of HAART has significantly reduced the frequency of CMV retinitis; however, a new entity i.e. immune recovery uveitis (IRU) has emerged as a complication of this therapy.
Thorne et al. (Ophthalmology 2006; 113:1441-5) concluded that in the HAART era, Zone 1 involvement and retinal detachment remained the most common causes of visual acuity loss among patients with CMV retinitis. Cataract and CME were also common causes of loss of visual acuity; primarily in patients with HAART-induced immune recovery.
Thorne et al. (Ophthalmology 2006; 113:1432-40) in a separate article concluded that CMV retinitis was associated with a substantial risk of incident vision loss even in the era of HAART. Those who had HAART-induced immune recovery had approximately 50% lower risk of visual acuity loss. Presence of IRU at baseline attenuated the protective effect of immune recovery for moderate vision loss but not for blindness.
Roels P (Optometry 2004;75(10):624-8) in a study observed that HAART effectively reduces the incidence of AIDS-related ophthalmic infections, such as CMV retinitis. Further, AIDS patients with CMV are less likely to experience necrotizing retinitis and retinal detachment. Incidence of Kaposi′s sarcoma has declined by an estimated 87% and molluscum contagiosum is seen less frequently in those using HAART.
Rauz and Murray (Sex Transm Infect. 1999;75(1):18-20) in their study reported a dramatic downturn in the number of new cases of CMV retinitis, which could be attributed to the introduction of HAART. Whereas paucity of inflammation has been considered to be the hallmark of the ophthalmic manifestations of AIDS, with immune recovery, a new pattern of ophthalmic AIDS has emerged, which is characterized by a heightened inflammatory response and complications like vitritis and cystoid macular edema (CME).
Canzano et al. (Retina1998;18(5):443-7) reported the occurrence of vitreomacular traction syndrome (VMT) following HAART-related immune recovery vitritis in cases of CMV retinitis. Changes in immune status may permit an inflammatory response that can lead to VMT.
Arevalo et al. (Ophthalmic Surg Lasers1997;28(4):321-4) performed analysis of vitreous cytology in rifabutin-related uveitis. Presumed rifabutin-related uveitis is characterized by unilateral or bilateral anterior chamber inflammation with hypopyon accompanied by hyperemia, pain, photophobia, and vitritis and it occurs in patients who take a daily dose of 300 to 1800 mg of this drug. Vitreous cytology of this case showed acute inflammatory cells.
Arruda ( Rev Assoc Med Bras. 2004;50(2):148-52) in a study observed a rise in the number of patients with normal ophthalmologic examination and decreased number of cases of CMV retinitis and ocular toxoplasmosis in the post-HAART era.
Goldberg et al. (Retina 2005;25(5):633-49) in a similar study observed that in the pre-HAART era, CMV retinitis was the most common HIV-associated retinopathy, occurring in 20-40% of patients. Retinal detachment occurred in 24-50% of patients annually. Herpetic retinopathy and toxoplasma retinochoroiditis occurred in 1-3% of patients and Pneumocystis carinii choroiditis, syphilitic retinitis, tuberculous choroiditis, cryptococcal choroiditis, and intraocular lymphoma occurred infrequently. In the HAART era the incidence of CMV retinitis has declined by 80%. Immune recovery in patients on HAART has allowed safe discontinuation of maintenance therapy in patients with regressed CMV retinitis and other HIV-associated retinopathies. Immune recovery uveitis is a HAART-dependent inflammatory response that may occur in up to 63% of patients with regressed CMV retinitis and elevated CD4 counts and is associated with vision loss from epiretinal membrane, cataract, and CME.
Garweg (Klin Monatsbl Augenheilkd. 2000;216(2):61-7) observed that since the introduction of HAART, although direct infectious destruction of tissue is less severe, inflammatory infiltration is augmented that may result in misinterpretation. Further, new disease entities have emerged like IRU, and Cidofovir and Rifabutin induced uveitis, which involve mainly the anterior uvea and vitreous.
Whitcup et al. (JAMA 2000;283(5):653-7) observed that with the introduction of HAART, retinitis did not progress in some patients when specific anti-CMV therapy was discontinued, but a number of patients developed substantial intraocular inflammation, which resulted in decreased visual acuity. Anterior uveitis, cataract, vitritis, CME, epiretinal membrane, and disc edema may occur in patients with CMV retinitis who showed HAART-associated elevation in CD4+ cell counts. Since IRU does not occur in eyes without CMV retinitis, the ocular inflammation appears to be related to the CMV infection.
Immune recovery uveitis
Lin et al. ( Ocul Immunol Inflamm. 2008;16(3):83-7) reported that symptomatic IRU develops in a significant number of patients with inactive CMV retinitis following successful HAART. Eyes with IRU respond favorably to anti-inflammatory therapy without reactivation of retinitis.
Garweg et al. (Ther Umsch. 2001;58(1):21-7) observed that IRU is a consequence of immune reconstitution in patients with a history of viral retinitis, which at times may be indistinguishable from reactivated retinitis.
Kedhar et al. (Herpes 2007;14(3):66-71) concluded that with sustained immune recovery due to HAART, discontinuation of anti-CMV therapy has been possible in many patients. Still, immune recovery does not guarantee protection from recurrent disease. CMV retinitis and uveitis associated with immune recovery still remain significant causes of vision loss and demand vigilance on the part of physicians.
Morrison et al. ( Ophthalmology 2007;114(2):334-9) evaluated the use of intravitreal triamcinolone (IVTA(20 mg)) for the treatment of macular edema secondary to IRU in eight eyes of seven patients with AIDS. Visual acuity improved at all time points and was statistically significant at the one-month and three-month follow-up examinations. The average visual improvement was three lines at three months. Retinal volume and thickness improvement were statistically significant at all time points. All patients had a minimum follow-up of nine months, and there was no case of CMV reactivation.
Kempen et al. (Ophthalmology 2006;113(4):684-94) in their study noticed that among eyes of patients with immune recovery, the prevalence of IRU is substantial. Eyes with IRU had a high risk of additional morbidity over and above that seen with CMV retinitis, with several-fold higher risk of CME and epiretinal membrane. Large CMV lesions and use of intravitreous cidofovir were risk factors for IRU.
Schrier et al. (Retina 2006;26(2):165-9) investigated immune and viral contributions to the pathogenesis of IRU. Aqueous and vitreous fluids from patients with IRU, active CMV retinitis, and control (HIV-negative, noninflamed eyes) were compared for presence of cytokines, IL-6, IL12, and interferon gamma using enzyme-linked immunosorbent assay techniques, and CMV DNA by polymerase chain reaction. They concluded that inflammatory IRU can be differentiated from active CMV retinitis by the presence of IL-12, less IL-6, and absence of detectable CMV replication.
Karavellas et al. (Am J Ophthalmol. 2000;130(1):57-64) performed a study to identify and describe long-term posterior and anterior segment complications of IRU in patients with inactive CMV retinitis who have HAART-mediated recovery of immune function. Persistent inflammation in IRU may lead to vision-threatening complications, such as proliferative vitreoretinopathy, posterior subcapsular cataract, and severe postoperative inflammation. They concluded that IRU is a chronic inflammatory syndrome that may result in complications months to years after the onset of inflammation.