PEER REVIEWED

Infectious Retinitis: A Review

YACHNA AHUJA, MD · STEVEN M. COUCH, MD · RAYMUND R. RAZONABLE, MD · SOPHIE J. BAKRI, MD

Infections of the retina are potentially devastating diseases because they can lead to permanent vision loss. Often, infectious retinitis is the initial clinical manifestation of a more systemic illness. Infectious retinitis affects both immune-competent and immune-compromised individuals. While seroepidemiologic studies reveal that certain pathogens such as cytomegalovirus (CMV) are ubiquitous in humans, retinitis caused by CMV is uncommon and is observed mainly in individuals with compromised cell-mediated immunity such as those with advanced AIDS. Likewise, retinitis caused by Toxoplasma gondii is seen more commonly in individuals with impaired immune function. On the other hand, certain infectious retinitis, such as that due to tuberculosis or syphilis, occur regardless of the immune status of the host, and in some cases, such as tuberculous retinitis, it is seen more commonly in endemic areas. Infectious retinitis requires early and aggressive treatment in order to avoid its potentially blinding outcome. The type of treatment relies on pathogen identification, and, in many cases, systemic administration of anti-infective therapy is required in view of underlying systemic infectious disease syndrome and to prevent the involvement of the contralateral eye. This article reviews a selected list of the more common endogenous infections affecting the retina with the aim of discussing disease pathogenesis, clinical presentation, diagnosis, and treatment.

CYTOMEGALOVIRUS RETINITIS

Cytomegalovirus, an enveloped double-stranded DNA virus belonging to the Herpesviridae family, is a common human infection with estimated seroprevalence rates reaching 90% to 100% in some populations. Several modes of transmission occur, including in utero (congential infection) and through urine, saliva, breast milk, sexually transmitted fluids, organ transplantation, and blood transfusion. Primary CMV infection universally leads to a latent state in many cells, which serve as reservoirs for transmission and reactivation during periods of immunodeficiency. Acute CMV infection during pregnancy can lead to congenital infection of the immunologically immature fetus, and up to one-quarter of infants with symptomatic congenital CMV infection manifest with retinitis.^1,2 Reactivation of latent CMV in immunosuppressed individuals, such as those with AIDS (when CD4+ T cell count is <50 cell/mm³) or organ and stem-cell transplant recipients, leads to disseminated disease involving several organs, including the retina.³

However, during the past 10 years, with earlier detection of human immunodeficiency virus infection and initiation of highly active antiretroviral therapy (HAART), CMV retinitis is becoming less commonly seen in patients with AIDS. Compared to patients with AIDS, CMV retinitis is less commonly seen in recipients of organ and stem-cell transplantation.⁶

Cytomegalovirus causes full-thickness retinal necrosis with pathognomonic cytomegalic cells with intranuclear inclusions.⁷ Clinically, CMV retinitis presents with blurred vision and floaters, especially in those with lesions in the posterior pole. CMV papillitis, which affects less than 10% of eyes, may present with sudden loss of vision.^8,9 Examination generally reveals 1 to 2 lesions in each eye that can be adjacent to blood vessels and in 1 or more of 3 zones.¹⁰ Zone 1 lesions are 1 to 2 disc diameters from the fovea and the optic nerve, and they are associated with sudden reductions in visual acuity (VA). Zone 2 lesions are located up to the vortex veins, with zone 3 extending from zone 2 to the ora serrata. Zone 3 lesions are highly associated with retinal detachments.^11,12 The hallmark CMV lesion is white with irregular granular borders, associated hemorrhage, and small "satellites" at the advancing edge (Figure 1). The associated vitritis and anterior uveitis are usually mild. There are 2 distinct variants of CMV retinitis.¹³ "Fulminant" lesions have marked edema with confluent areas of retinal whitening, retinal hemorrhage, and vascular sheathing. "Indolent" lesions are round granular lesions in the peripheral retina, with little associated edema and faint opacification.¹⁴ Untreated CMV lesions usually enlarge rapidly, with the entire retina being destroyed within 6 months or less, especially in individuals with persistent immune compromise.¹⁵

Figure 1. Classic CMV retinitis extending along inferotemporal arcade. Note the white area of inflammation with associated hemorrhage and satellite lesions at advancing border.

The diagnosis of CMV retinitis is primarily based on clinical grounds, although CMV detection by polymerase chain reaction (PCR) of aqueous and vitreous humor can be done for atypical cases.^16,17 In some cases, CMV may be detected in blood and other body fluids, although in many cases, CMV retinitis is compartmentalized. Treatment of CMV retinitis involves an induction phase, with high doses of anti-CMV agents, followed by a maintenance phase, which is aimed at both halting the progression and preventing the recurrence of disease. The most common agent used is intravenous (IV) ganciclovir (Cytovene, Roche) or its oral alternative, valganciclovir (Valcyte, Roche). Ganciclovir can also be given through intravitreous route, as an injection or an implant (Vitrasert, Bausch & Lomb, Rochester, NY). Oral ganciclovir should not be used for treatment since it is poorly absorbed and has low bioavailability. Other alternative drugs are IV foscarnet (Foscavir, AstroZeneca) and cidofovir (Vistide, Gilead Sciences, Foster City, CA). All 3 drugs are virostatic and halt CMV replication by inhibiting CMV DNA polymerase. In contrast, a fourth anti-CMV drug, fomivirsen (Vitravene, Isis Pharmaceuticals, Carlsbad, CA), acts through an antisense mechanism.¹⁸

The most common initial treatment course for CMV retinitis in patients with AIDS includes IV ganciclovir at a dose of 5 mg/kg twice daily for 3 weeks, followed by maintenance therapy with either IV ganciclovir or oral valganciclovir. At a dose of 900 mg orally per day, valganciclovir achieves similar serum concentrations as IV ganciclovir 5 mg/kg,¹⁹ and, hence, valganciclovir, at a dose of 900 mg twice daily for 3 weeks, has been shown to be equally effective and comparable to IV ganciclovir for induction treatment of CMV retinitis in patients with AIDS. The use of the ganciclovir implant has led to a much longer median time to progression of CMV retinitis compared to IV ganciclovir.^20,21 Though ganciclovir is associated with bone marrow suppression, systemic administration of ganciclovir is highly recommended — even in patients treated with the ganciclovir implant since CMV disease is often a disseminated illness — to prevent the involvement of the contralateral eye. The use of IV foscarnet is limited by side effects of electrolyte disturbance and nephrotoxicity.²² Intravenous cidofovir has a long half-life, enabling its once weekly dosing.²³ However, cidofovir is highly nephrotoxic and is associated with sight-threatening uveitis and hypotony; hence, it is less commonly used. Clinical trials with fomivirsen have shown that it is effective for CMV-retinitis refractory to other drugs, and it also increases the time to disease progression.^24,25 Drug resistance can develop during treatment with each of these agents, particularly in patients with persistent immune compromise and with the use of poorly bioavailable agents such as oral ganciclovir.^26,27

The most common complication of CMV retinitis is retinal detachment. In AIDS patients with CMV retinitis, it is important to start HAART therapy, although immune recovery uveitis can develop with its initiation,^28-30 and this can lead to severe vision loss and may require treatment with anti-inflammatory agents.

ACUTE RETINAL NECROSIS AND PROGRESSIVE OUTER RETINAL NECROSIS SYNDROMES

Varicella zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 have been implicated as the etiologic agents of progressive necrotizing retinopathies including acute retinal necrosis (ARN), which is classically described in immunocompetent patients, and progressive outer retinal necrosis (PORN) syndrome, which is seen in immunocompromised patients.

Acute retinal necrosis, which may involve one or both eyes of healthy patients (and less commonly, in immunocompromised patients)^31-33 is characterized by anterior uveitis, vitritis, and retinal vasculitis with patchy or confluent areas of cream-colored retinal necrosis (Figure 2) that initially affects the peripheral retina and then extends posteriorly, often leading to retinal detachment.^34-37 The diagnosis of ARN is based on clinical grounds and supported by demonstration of the offending herpes virus with techniques such as PCR of intraocular specimens.^38-40 In contrast, PORN is seen in immunocompromised patients with a paucity of uveal inflammation and vasculitis, characterized mainly by outer retinal discoloration in the posterior pole, which spreads rapidly throughout the fundus.⁴¹

Figure 2. Acute retinal necrosis, showing an advancing border of necrosis with atrophic areas and holes.

Although there are limited reports of successful combination antiviral treatment for PORN with acyclovir, foscarnet, and ganciclovir, PORN usually shows rapid progression and carries a very poor prognosis.^42,43 The management of ARN varies, depending on the severity of disease.⁴⁴ Antiviral treatment should be given promptly, with either IV acyclovir, oral valaciclovir, or famciclovir (Famvir, Schering-Plough).^45-47 A common treatment strategy is IV acyclovir 1500 mg/m², divided every 8 hours for 7 days followed by 4 to 6 weeks of oral acyclovir, 2 to 4 g/day.⁴⁴ Systemic and topical corticosteroids are often added to minimize the inflammatory damage to the optic nerve and blood vessels.⁴⁸ Since many severe cases also involve an occlusive vasculitis, low-dose aspirin is added as antithrombotic treatment.^49,50 Surgery may be needed to repair rhegmatogenous retinal detachments. Prophylactic argon laser treatment has been used to reduce the risk of this complication, although its use is controversial in the treatment of ARN. The visual prognosis of ARN is poor, particularly in cases caused by VZV.^51-54

ENDOGENOUS FUNGAL INFECTIONS OF THE RETINA

Fungal infections of the retina are among the most devastating ocular infections.⁵⁵ Two types occur according to mode of acquisition. Endogenous fungal retinitis occurs as a component of disseminated fungal diseases, while exogenous fungal retinitis occurs after ocular trauma or surgery. The most common among these infections is candidal chorioretinitis, usually caused by Candida albicans, although other species of candida have also been observed.⁵⁶ Factors that could predispose to candidemia and candidal chorioretinitis include recent major surgery, bacterial sepsis, indwelling intravenous catheters,^57-60 and intravenous drug abuse.^61,62 Candidal retinitis is also the most common intraocular fungal infection of newborns.^63,64 Endogenous candidal chorioretinitis usually presents with decreased vision, as well as pain due to associated anterior uveitis or iridocyclitis. The vitreous is typically hazy, overlying a white circumscribed lesion of less than 1 mm in diameter (Figure 3). Diagnosis is usually clinical, although the vitreous humor can be cultured.⁶⁵

Figure 3. Candidal endophthalmitis. Vitreous inflammation obscures some details of the photograph; however, the dense fluffy localized infiltrate is characteristic.

Aspergillus species is the second most common fungal group that infects the choroid and retina. Aspergillus fumigatus retinitis is seen mostly among intravenous drug abusers, patients who have received transplants, and those with malignancy and chronic lung diseases.^66-69 The lesions are characterized as yellow subretinal and retinal infiltrates in one or both eyes, associated with rapid vision loss, severe inflammation, and retinal hemorrhage.⁷⁰ Aspergillus species is a highly vasculotrophic fungus. Retinal vessels can be invaded, resulting in thrombosis, infarction, and retinal necrosis.⁷¹ In severe disease, septate branching hyphae can be found throughout the eye. This is usually associated with disseminated disease and pulmonary involvement. Serologic tests are not helpful and cultures of the blood are often negative.⁷²

Cryptococcus neoformans is a common cause of intraocular fungal infection in AIDS patients.^73-75 Ocular involvement is frequently associated with cryptococcal meningitis, although retinal lesions may also be present without or prior to the onset of meningitis.^76,77 Initial symptoms are intermittent blurring of vision that can progress to severe endophthalmitis with associated meningeal or systemic infection.^78,79 Multifocal chorioretinitis is the most common finding with yellowish-white fundus lesions of various sizes and associated mutton-fat keratic precipitates, exudative vitreous detachment, and vitritis.^80,81

The prevalence of intraocular fungal infections may have decreased over the past decade due to availability of well-tolerated antifungal agents for prophylaxis in immunocompromised patients, the early initiation of systemic antifungal therapy based on positive blood cultures, and the recovery of immune function in patients with AIDS who are receiving HAART.^82,83 When it occurs, however, fungal ocular infection should always be treated, since failure to treat usually results in severe endophthalmitis and vision loss.⁸⁴ The drugs that may be used for the treatment should be guided by the specific fungal pathogen. While conventional and lipid formulations of amphotericin B have traditionally been considered as the drugs of first line, their use is limited by systemic toxicities, including renal failure and anaphylaxis.⁸⁵ Flucytosine is sometimes combined with amphotericin B to facilitate fungal clearance, although flucytosine should never be used alone because of the rapid development of drug resistance.⁸⁶

The azole class of antifungal drugs offers a well-tolerated regimen for the treatment of many fungal infections. Fluconazole (Diflucan, Pfizer) is effective as treatment for C. albicans retinitis or as a "step-down" treatment after initial treatment with amphotericin B, although other studies have noted treatment failure.^87-90 Newer triazoles such as voriconazole (VFEND, Pfizer) and posaconazole (Noxafil, Schering-Plough) have supplanted amphotericin B for the treatment of invasive aspergillosis. Voriconazole has been demonstrated to have good ocular penetration, and thus it has been reported as useful for the treatment of fungal retinitis.^91-93 The echinocandins, such as caspofungin (Cancidas, Merck), micafungin (Mycamine, Astellas), and anidulafungin (Eraxis, Pfizer), are highly active against Candida species and Aspergillus species (but not C. neoformans); however, poor penetration into the ocular compartments is a concern and their utility for the treatment of fungal retinitis is therefore questionable. Due to the common association with systemic disease, the intravenous and oral route is generally used for the administration of antifungals in the treatment of endogenous fungal endophthalmitis; however intraocular antifungal therapy with agents such as amphotericin B and voriconazole also has an important adjunctive role.⁹⁴ Vitrectomy is a useful adjunct therapy if there is severe vitreous involvement or failure of medical therapy.^95.96

OCULAR TOXOPLASMOSIS

Ocular toxoplasmosis is a potentially blinding retinitis caused by the obligate intracellular parasite T. gondii. Felines are the definitive hosts of the parasite, but it can be transmitted to humans through contaminated meat and eggs.^97,98 T. gondii can persist as latent infection in humans for many years by living within host-cell vacuoles (tissue cysts) in any organ. In immunocompromised hosts, the cyst ruptures and leads to dissemination of T. gondii to cause systemic illness that includes panophthalmitis and retinitis.⁹⁹

Within the eye, tissue cyst rupture can cause an active focal necrotizing retinitis followed by scar formation.¹⁰⁰ This may be directly due to parasitic proliferation, while overlying effects such as vitritis and anterior uveitis may be due to a hypersensitivity response.¹⁰¹ Active lesions are identified as localized areas of infiltrate (Figure 4). Classically, these active lesions are adjacent to old inactive scars and focal vasculitis. The 3 morphological variants of these lesions are large destructive lesions, punctate inner retinal lesions, and punctate outer retinal lesions.¹⁰² Secondary complications, such as cataract, glaucoma, cystoid macular edema, and chorioretinal vascular anastomoses, can occur. A minority of patients may have toxoplasmic papillitis, where the foci of inflammation are adjacent to the optic nerve head.¹⁰³

Figure 4. Toxoplasma gondii retinochoroiditis. Notice the well-circumscribed area of retinochoroidal edema.

Symptoms of ocular toxoplasmosis include floaters or reduced vision. In children with congenital toxoplasmosis, initial signs include nystagmus or strabismus, with over 80% developing retinochoroiditis by adolescence. Of these cases, up to 40% are bilateral.¹⁰⁴ The diagnosis of ocular toxoplasmosis is based on characteristic retinal scars, supported by serologic antibody tests such as the indirect fluorescent antibody test and the enzyme-linked immunosorbent assay (ELISA) tests. Definitive diagnosis is difficult since there is high prevalence of antibodies in healthy adults, although the presence of immunoglobulin M antibodies would indicate acute infection.¹⁰⁵

The decision to treat ocular toxoplasmosis is based on the location of lesions, the extent of secondary effects, and the immune status of the human host. Large destructive lesions and posterior-pole lesions are associated with severe vision loss and are treated. Lesions that are small and peripheral may heal without treatment. Immunocompromised patients may require treatment regardless of the extent of the lesion at diagnosis. The most common treatment regimen includes the combination of pyrimethamine (Daraprim, GlaxoSmithKline) and sulfadiazine, and often corticosteroids are added.¹⁰⁶ The addition of folinic acid to this regimen prevents leucopenia and thrombocytopenia due to pyrimethamine treatment. Therapy with trimethoprim-sulfamethoxazole or pyrimethamine-azithromycin has been shown to have equal efficacy and is considered an acceptable regimen for the treatment of ocular toxoplasmosis.^107,108 Prophylactic pyrimethamine-sulfamethoxazole may be useful for recurrent attacks of ocular toxoplasmosis or after cataract extraction when there is a potential risk of reactivation.^109,110 The use of prophylactic trimethoprim-sulfamethoxazole has reduced the incidence of toxoplasmosis after transplantation. The overall prognosis is usually good in immunocompetent individuals, as long as the central macula is not involved.¹¹¹

OCULAR TOXOCARIASIS

Ocular toxocariasis is a common diagnosis in asymptomatic children and it is a major worldwide cause of vision loss.^112-114 The roundworm Toxocara canis is transmitted by ingestion of fertilized ova, followed by systemic dissemination via the circulatory system. Systemic toxocariasis can range from mild eosinophilia to fatal disease involving pneumonia, congestive heart failure, or convulsions.^115,116 Children who develop ocular toxocariasis are usually older and often do not have a history of prior systemic infestation. There is usually a history of pica and exposure to puppies.^117,118 Vision loss occurs from damage to the vitreous and retina due to an inflammatory response to T. canis.¹¹⁹

Toxocara endophthalmitis may present in 3 classic forms: chronic endophthalmitis, posterior pole "granuloma," and peripheral inflammatory mass. There is no external inflammation in the chronic endophthalmitis form.¹²⁰ An acute inflammation phase with associated anterior granulomatous response and yellowish-white infiltrates in the vitreous and retina may either subside or be followed by fibrocellular membrane development deep within the vitreous.¹²¹ Prognosis depends on the extent of intravitreous organization. The posterior pole granuloma form usually presents with strabismus. The vitreous is hazy with an ill-defined posterior pole mass that becomes well-defined as a gray granulomatous mass as the initial inflammation subsides (Figure 5). Visual prognosis is usually good with stable vision, although there is usually already some loss of central vision by the time of diagnosis.¹²² The peripheral inflammatory mass form may be preceded by acute diffuse endophthalmitis. As the inflammation subsides, a peripheral dense white mass becomes apparent, which is either diffuse or spherical.¹²³ Prognosis is relatively good, although surgical treatment, such as scleral buckling and vitrectomy, may be required if there are associated intraretinal bands and resultant retinal detachment.^124-126

Figure 5. Toxocara canis retinitis.

The diagnosis of ocular toxocariasis is usually made by using serum and intraocular fluids for ELISA testing and cytology analysis.^127-129 Patients frequently do not have serum eosinophilia, although the presence of eosinophils in aqueous humor or vitrectomy specimens suggests the infection.¹³⁰ Treatment, depending on the stage and secondary effects of the disease, is controversial due to the theoretical risk of worsened inflammation when the intraocular organism is killed. For cases when the mobile larvae can be found, direct laser photocoagulation may be useful.¹³¹ Studies show the benefit of using albendazole or thiabendazole with topical or periocular injections of corticosteroids.^132-134

OCULAR TUBERCULOSIS

Tuberculosis, an airborne infection caused by Mycobacterium tuberculosis, most commonly affects the lungs, although extrapulmonary manifestations are not uncommon. Histologically, tuberculous lesions are characterized by caseating granulomas.¹³⁵ Among the extrapulmonary manifestations, intraocular tuberculosis is believed to result from hematogenous spread of the bacilli.¹³⁶

The most common presentation is posterior uveitis followed by anterior uveitis and panuveitis (Figure 6).¹³⁷ Tubercular retinal vasculitis is also common and is associated with vitreous infiltrates, retinal hemorrhage, neovascularization, and neuroretinitis.^138-140 Posterior involvement can be divided into 4 forms: choroidal tubercles, choroidal tuberculoma, subretinal abscess, and serpiginous-like choroiditis. The most common is multiple choroidal tubercles, which appear as small grayish nodules in the posterior pole of one or both eyes (Figure 7). These usually respond well to treatment and take up to 4 months to heal.^141-143 Choroidal tuberculoma, a less common presentation in which hemorrhages and retinal folds may be seen on the tuberculoma surface,¹⁴⁴ may be misdiagnosed as an intraocular tumor.^145-147 Subretinal abscesses are yellow necrotizing granulomas that usually heal with treatment and have a good prognosis.^148,149 Serpiginous-like choroiditis is a recurrent inflammation that involves the choroid and progresses to the retina, despite systemic corticosteroids and immunosuppressive agents. Additionally, the fellow eye may be affected months or years later.^150,151

Figure 6. Granulomatous uveitis associated with intraocular tuberculosis. A Koeppe nodule is noted at the 11:00 position.

Figure 7. Tuberculous retinochoroiditis.

The diagnosis of intraocular tuberculosis should be suspected based on clinical grounds. These can be supported by a positive purified protein derivative skin testing and chest X-ray suggestive of pulmonary involvement.¹⁵² Newer diagnostic modalities include assessment of interferon-gamma release in assays such as QuantiFERON Gold TB test (Cellestis, Ltd., Carnegie, Australia).¹⁵³ Direct isolation or demonstration of the acid-fast bacilli in the ocular fluid or tissue or the detection of the M. tuberculosis genome by PCR and other nucleic acid amplification techniques confirms the diagnosis of tuberculosis.^154-158

The treatment of ocular tuberculosis is similar to that for pulmonary or extrapulmonary tuberculosis. This includes at least 3 drugs (isoniazid, rifampin, and pyrazinamide, with or without ethambutol) for 2 months, followed by isoniazid and rifampin for the next 7 months.^159,160 Some studies have described treatment of ocular tuberculosis for 9 months with isoniazid and rifampin, although this is not ideal and currently not the standard of care.^161-163 The final choice of antibiotic therapy should be guided by susceptibility testing. Second-line agents, such as streptomycin, capreomycin, and quinolones, are often reserved for cases due to multi–drug-resistant tuberculosis.^164,165

OCULAR SYPHILIS

Ocular syphilis is caused either by the direct invasion of the spirochete Treponema pallidum or by an allergic reaction in tissues sensitized by the pathogen. Studies show that the incidence of ocular syphilis is on the rise over the past decade, possibly as the result of high-risk behavior associated with the spread of AIDS.^166-168

Ocular syphilis has different manifestations depending on its time of onset. Congenital syphilis is usually associated with a pigmentary retinopathy that appears somewhat like retinitis pigmentosa. This retinopathy may be segmental or generalized, and it can present in either patients without any prior symptomatic inflammatory episodes or in those who have had an episode of syphilitic interstitial keratitis.^169,170 In acquired syphilis, there is usually a patchy diffuse neuroretinitis that can have hemorrhagic areas. Flare and cells can be seen in the anterior and posterior segments. Clinically, there is reduced VA and contraction of the visual fields.¹⁷¹

Syphilis is diagnosed serologically with the rapid plasma reagin (RPR) test, followed by the more sensitive fluorescent treponemal antibody absorption test (FTA-ABS).¹⁷² Serum RPR can be negative in some cases of neuroretinitis despite a positive FTA-ABS test; thus, in such cases, a lumbar puncture can be useful to assess spinal fluid involvement. The primary treatment for syphilis is penicillin G. Ocular syphilis is often considered as a type of central nervous system disease and therefore, as with neurosyphilis, a high dose of 10 million units of penicillin given intravenously daily for 10 to 14 days is required.¹⁷³ For penicillin-allergic patients, ceftriaxone and doxycycline are effective alternatives, although penicillin desensitization may be attempted, especially in pregnant women.¹⁷⁴ Early treatment of syphilitic neuroretinitis can result in improvement of VA and expansion of the visual fields.¹⁷⁵

CONCLUSIONS

Infectious retinitis represents a spectrum of ophthalmic diseases that are potentially preventable and treatable. The foregoing discussion of selected infectious retinitides illustrates the wide array of potential pathogens from viruses to fungi, bacteria, and parasites. It also highlights its occurrence in both immune-competent and immune-compromised hosts. While the pathogens and the hosts vary widely, prevention of the devastating outcome of vision loss is the uniform goal of management. In this regard, knowledge of the offending pathogen, its typical clinical manifestations, and its anti-infective susceptibility pattern are essential to successful treatment. Likewise, knowledge of the immune status of the host is essential, since immune-modifying strategies may be needed to complement the anti-infective treatment, because infectious retinitis is much more aggressive and has a poorer outcome in immune-compromised patients. Finally, recognizing that infectious retinitis is often a component of a more systemic illness is important in the successful management of the disease. RP

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