Immune recovery uveitis involvement of the eye in immune reconstitution inflammatory syndrome

Since the advent of the so-called combined Anti Retroviral Therapy (cART) the Immune Reconstitution Inflammatory Syndrome (IRIS) has emerged as an important condition complicating antiretroviral treatment: 10-25% of patients receiving cART may develop atypical forms of (opportunistic) infections (OI), presenting with unusually enhanced inflammatory reactions. Because the clinical symptoms worsen while under therapy, these manifestations are referred to as paradoxical. The term “unmasking syndrome” (regarded by some as a distinct form of IRIS), is used in case symptoms of a previously subclinical OI become manifest. Such reactions are attributed to dysregulation of immunological responses to antigens from opportunistic pathogens in a partially restored immune system. IRIS typically occurs during the initial phase of cART (highest incidence 8-16 weeks after initiation [1]), and is associated with a wide spectrum of pathogens, most commonly mycobacteriae, herpes viruses, and fungal infections such as cryptococcal meningitis. Patients with advanced immune deficiency (CD4 cell counts fewer than 50/μL) have the highest risk of developing IRIS.

Ocular immune reconstitution phenomena

Soon after the introduction of cART, enhanced ocular inflammation (diagnosed by the presence of cells and flare in the eye) was observed in the anterior chamber and vitreous cavity of patients with inactive CMV-retinitis (CMV-R). This uncommon phenomenon typically occurred within 6-12 weeks after initiation in patients with advanced immune depletion [2,3]. Classically, the clinical picture of CMV-R in AIDS is characterized by only minor inflammation in these compartments as a result of the inability to mount inflammatory responses due to severe immune incompetence. Now, enhanced inflammation seemed to be associated with a rapid increase of CD4 cell counts to values above 100/μL, and was attributed to enhanced immunological responses against CMV antigens as a result of cART. Because this ocular form of IRIS presents as uveitis, it is usually referred to as ‘immune recovery uveitis’ (IRU).

Apart from CMV-R, other (opportunistic) infections, such as mycobacterial infections [4] and infection with Leishmania major [5] have also been associated with IRU.

Clinic

The clinical spectrum of IRU expands from asymptomatic in some patients, to acute onset and self-limiting course (transient vitritis) [2], and to chronic persisting uveitis with long term complications [3].

For symptomatic cases of IRU, visual loss and floaters are the most common presenting symptoms. IRU-induced permanent loss of vision may result from complications of the intraocular inflammation, most commonly cystoid macular edema (CME) and epiretinal membrane formation, reflecting the primarily posterior segment location of inflammation in most cases [3,6].

Diagnosis and treatment

The diagnosis IRIS (IRU) is usually made on the basis of clinical evidence of newly developed or enhanced (intraocular) inflammation in HIV-positive individuals with advanced immune deficiency, shortly after receiving cART.

While inflammation in IRIS generally can be mitigated by corticosteroids, infectious diseases require a different approach, namely control of the underlying infectious agent, in which corticosteroids are often contraindicated. Unmasking IRIS should be differentiated from co-infections (e.g. tuberculosis, syphilis) and other disseminated (O)Is, systemic diseases, and primary manifestations of (ocular) infection. One should always be alert to distinguish whether the symptoms result from a process of restoration of the immune system due to cART, or rather should be regarded as the expression of a (disseminated) infection in a still immune incompetent individual. Obviously, to justify the diagnosis IRIS, a certain degree of immune recovery should be achieved (rise in CD4 cell count by >50/μL to a level > 100/μL [7]). This reflects a degree of immune recovery expected to control CMV in the absence of anti-CMV therapy.

Unmasking forms of IRIS generally require treatment of the causative pathogen, with simultaneous mitigation of the destructive inflammatory reaction. IRU in case of active CMV-R requires anti-CMV medication until under cART a substantial and sustained rise in CD4 cells has been achieved. In cases of mild and more advanced IRU, topical or orbital floor corticosteroids are usually sufficient to control inflammation. This therapy may also be beneficial for CME, and improve vision, at least in the short run. Established CME associated with IRU however, can follow a chronic course that is refractory to therapy.

Prevention

It is probable that most cases of IRIS can be prevented by early identification of HIV-infected patients, and initiation of cART before they reach the advanced stage of immune deficiency associated with a high risk of OIs. Primary treatment of systemic OIs for a short period preceding initiation of cART may be indicated. Some investigators believe that a similar approach may reduce the incidence of CMV-associated IRU. However, because CMV retinitis is associated with a very high risk of mortality especially in the absence of cART, even a short delay in the initiation of cART should be avoided [8]. Only very rare circumstances would justify discontinuation of cART in case of IRU [9].

Further research into the incidence and outcome of IRU, especially in resource-poor regions, is needed to better clarify the extent of this evolving problem in the regions of highest HIV prevalence.

References

1. French MA, Lenzo N, John M, Mallal SA, McKinnon EJ, James IR, Price P, Flexman JP, Tay-Kearney ML. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV.Med. 2000; 1:107-15.
2. Van den Horn GJ, Meenken C, Danner SA, Reiss P, de S. Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV+ patients. Br.J.Ophthalmol. 1998; 82: 988-90.
3. Karavellas MP, Plummer DJ, MacDonald JC, Torriani FJ, Shufelt CL, Azen SP, Freeman WR. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J.Infect.Dis. 1999; 179: 697-700.
4. Zamir E, Hudson H, Ober RR, Kumar SK, Wang RC, Read RW, Rao NA. Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis? Ophthalmology 2002; 109: 2144-8.
5. Meenken C, van Agtmael MA, Ten Kate RW, van den Horn GJ: Fulminant ocular leishmaniasis in an HIV-1-positive patient. AIDS 2004; 18: 1485-6.
6. Jabs DA, Van Natta ML, Holbrook JT, Kempen JH, Meinert CL, Davis MD: Longitudinal study of the ocular complications of AIDS: 2. Ocular examination results at enrollment. Ophthalmology 2007; 114: 787-93.
7. Kempen JH, Min YI, Freeman WR, Holland GN, Friedberg DN, Dieterich DT, Jabs DA. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006; 113: 684-94.
8. Otiti-Sengeri J, Meenken C, van den Horn GJ, Kempen JH: Ocular immune reconstitution inflammatory syndromes. Curr Opin HIV AIDS 2008; 3: 432-7.
9. Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. Epub 2009 May 18.

Some important Dutch non-government organizations in the field of eye care

WWW.ASIANEYECARE.NL
Projects in Cambodia, Vietnam and Myanmar for the prevention and treatment of blindness, including training.

WWW.EYECAREFOUNDATION.NL
Projects in Nepal, Vietnam, Cambodia, Laos and Tanzania. In Tanzania supporting training of ophthalmologists for Tanzania and surrounding countries.

WWW.FIGHTFORSIGHT.NL
Lions Working Group against blindness in cooperation with Wild Geese for support to small scale projects in Africa and Asia, cataract surgery, instruments, equipments, infrastructure, school screening and low vision programmes. May provide direct support for urgent needs.

WWW.LIGHTFORTHEWORLD.NL
Projects in Africa and Asia for the prevention of blindness and visual impairment, for education and rehabilitation and for local capacity building.
(Previously known as Foundation Dark & Light)

HTTP://SLAH.NL
Stichting Leer Anderen Helpen. Projects in Indonesia among less privileged populations. Treatment and training.