- Christian Hoffmann -
For the first time, in mid-1997 and early 1998, two groups described atypical manifestations of CMV retinitis (Jacobsen 1997) and MAC disease with abscess formation (Race 1998) in HIV patients within a few weeks of initiation of ART. Although the pathogens, pathogenesis and localization were very different, all these illnesses had a distinct inflammatory component and were associated with significant immune reconstitution in these patients. Consequently, suspected early on that these presentations could constitute a syndrome during which a latent infection present at initiation of therapy is fought more effectively by the recovering immune system (Overview: French 2009). Infections are not the only cause of an IRIS. Malignancies and other diseases have also been decribed as IRIS-related (see below).
The International Network for the Study of HIV-associated IRIS (INSHI, http://www.med.umn.edu/inshi/) has established the following consensus criteria for diagnosis of IRIS:
1. Response to ART (at least one log10 copies/mL decrease in HIV RNA)
2. Clinical deterioration of an infectious or inflammatory condition temporally related to ART initiation.
3. Symptoms cannot be explained by expected clinical course of a previously recognized and successfully treated infection, medication side effect or toxicity, treatment failure or complete non-adherence.
One must differentiate between subclinical infections first appearing on ART (“unmasking IRIS”) and clinically evident infections already existing at therapy initiation, which often paradoxically become worse during therapy (”paradoxical IRIS”).
IRIS in many publications today is often a collection of bizarre, sometimes grotesque case reports, which have actually only one common ground: an unexpected, usually clinically impressing infection, differing significantly from the courses of diseases seen during the pre-HAART era. Nevertheless, IRIS has three rules:
- Anything is possible.
- Nothing is as it was in the pre-HAART era.
- IRIS does not mean that ART has failed. In addition, the patients usually have a good prognosis.
How frequently does IRIS occur? Due to the lack of a definition in the early years of ART, the data vary substantially. In our experience, a frequency of 5-10% in patients with less than 200 CD4 T cells/µl is realistic. Very low CD4 T cells, a high viral load before initiation of therapy or a rapid drop of HIV RNA on ART seem to be important predictive factors for IRIS. If one focus on the patients who were already infected with mycobacteria or cryptococcus neoformans before ART was started, IRIS rates of 30% are reached (Müller 2010).
Mycobacterial IRIS. For MAC, the number of published cases with grotesque, fistular lymphadenitis, cutaneous or muscular abscesses, osteomyelitis, nephritis or meningitis is too large to be cited here. After a total of 83 patients started ART with a CD4 T cell count of less than 200/µl, only six mycobacterioses, among these four MAC infections were observed within the first weeks of beginning therapy (Hoffmann 1999). Lymph node abscesses usually occur during the first weeks on ART. IRIS cases with Mycobacterium xenopi or kansasii have also been described (Chen 2004, Phillips 2005).
There are now also numerous reports on tuberculosis (John 1998, Chien 1998), which are reminiscent of the “paradox” reactions to TB treatment known since the 1950s. All of these patients similarly suffered an initial deterioration under sufficient tuberculostatic treatment and ART-induced immune reconstitution. By the same token, meningitis as well as marked lymphadenopathy with unspecific histology can complicate the course of disease, yet both respond astonishingly rapidly and well to steroids. Prednisolone was very effective in a recent placebo-controlled trial (Meintjes 2010).
It is still not clear whether an early or immediate start of ART in therapy naïve patients facilitates the occurrance of an IRIS. In at least two large randomized trials (STIDE and SAPIT) the risk of an IRIS increased when ART was started immediately in patients with TB. In both studies, however, the increased risk did not lead to an increased mortality (Abdool 2011, Havlir 2011). A randomized study in patients with tuberculous meningitis contradicts these results showing less favorable effects for an early ART (Torok 2009).
CMV IRIS. In addition to mycobacteriosis, numerous cases of unusual CMV infections under ART have been published. In patients with previously diagnosed CMV retiniotis, IRIS developed in 38% (Müller 2010). Inflammatory CMV retinitis with vitritis that may lead to visual impairment, papillitis and macular edema, can now be described as a distinct syndrome, differing significantly from the course of CMV retinitis seen in the pre-HAART era (Jacobson 1997, Karavellas 1999). Neovascularization endangers vision even after resolution (Wright 2003). As with MAC disease, in vitro studies have shown that the CMV-specific immune response is improved most significantly in those patients developing vitritis (Mutimer 2002, Stone 2002). Inflammatory CMV manifestations are not limited to the retina and may involve other organs.
PML IRIS. The course of inflammatory PML that occurs during an IRIS is different from the infaust prognosis seen during the pre-HAART era (Collazos 1999, Kotecha 1998, Cinque 2001, Miralles 2001). Clinical symptoms are often more fulminant initially, and on radiology, there is a contrast enhancement which is otherwise atypical for PML, that may resolve over time. Patients have a better prognosis, and PML seems to even resolve completely (Hoffmann 2003, Du Pasquier 2003). It appears that a number of patients with inflammatory PML, who have been asymptomatic for years, live without any residual symptoms. However, fatal cases of inflammatory PML have also been reported (Safdar 2002). Previously documented experiences indicate that steroids are ineffective, although there have been accounts of positive results (Nuttall 2004, Tan 2009).
Cryptococcal IRIS. Numerous cases with inflammatory courses of disease have been described (Overview: Haddow 2010). Together with MAC/TBC and CMV, cryptococci are probably the most influential pathogens that contribute to an IRIS. In particular, severely immunocompromised patients who start with ART after cryptococcal therapy should be watched closely for the first few weeks and months. Newer studies show that 10-20% of patients with co-infections develop a cryptococcal IRIS (Sungkanuparph 2009, Müller 2010). The MRI usually shows choriomeningitis with significant enhancement in the choroid plexus. Cryptococcal antigen in the CSF is positive, although culture remains negative (Boelaert 2004). The intracranial pressure is often particularly high (Shelbourne 2005). As well as meningitis, lymphadenitis can also occur (Skiest 2005).
IRIS, induced by other infections. A variety of contemporary case studies have documented the induction of IRIS by the following infections: leishmaniasis (Jiménez-Expósito 1999), penicillosis (Ho 2010), histoplasmosis (De Lavaissiere 2008), pneumocystosis (Barry 2002, Koval 2002, Godoy 2008, Jagannathan 2009, Mori 2009), or herpes (Fox 1999). Herpes zoster and hepatitis B or C episodes also seem to occur on ART, particularly during the first weeks (Behrens 2000, Chung 2002, Manegold 2001, Martinez 1998, Domingo 2001). HHV-8-associated Kaposi’s sarcoma can worsen significantly on ART in the presence of an IRIS (Bower 2005, Leidner 2005, Feller 2008). Increasing dermatological problems such as exacerbation of pre-existing folliculitis or skin disease have also been reported (Handa 2001, Lehloenyia 2006, Pereira 2007, Iarikov 2008). There are even reports about parvovirus and leprosy (Nolan 2003, Couppie 2004, Bussone 2010, Watanabe 2011).
IRIS and other diseases. Diseases other than OIs are now recognized to occur under IRIS. These include autoimmune diseases such as Graves’ disease, lupus, Sweet’s and Reiter’s syndromes, Guillain-Barré syndrome, acute porphyria, gout and sarcoidosis, to name but a few (Bevilacqua 1999, Behrens 1998, Fox 1999, Gilquin 1998, Makela 2002, Mirmirani 1999, Neumann 2003, Piliero 2003, Sebeny 2010). Even two cases of Peyronie’s disease, a fibrosis of the penis, were reported (Rogers 2004). These reports do raise the question of whether all of these manifestations are truly induced by immune reconstitution or perhaps merely chance occurrences. While most reports initially offered little information on the etiology beyond purely hypothetical discussions, it has recently become apparent that changes in the cytokine profile are involved in the pathogenesis of IRIS, together with an activation of the cellular immune response. However, it seems that the mechanisms differ according to disease and genetic profile (Price 2001, Shelbourne 2005).
Patients starting ART with less than 200 CD4 T cells/µl and particularly those who have a high viral load require close clinical monitoring during the first weeks. Close attention should be give especially in cases where very immunocompromised patients who have previously declined antiretroviral treatment, suddenly feel physically “affected,” express subfebrile conditions, and want to start ART “after thinking about it for a long time.” Latent infections are often present in such cases and rapidly become apparent as immune reconstitution occurs – the poorer the immune status and the longer its duration, the greater the danger of IRIS. Although newer studies prove that infection parameters such as CROP, D-dimer or cytokines such as IL-6 or IP-7 are predictive for an IRIS or OI (Rodger 2009, Antonelli 2010, Porter 2010) it is not generally practiced in routine diagnosis.
However chest radiography, abdominal ultrasound and fundoscopy should be included in routine investigations of such patients before beginning treatment. Moreover, clinical examination which nowadays are often gladly overlooked should be taken seriously. Some authors suggest that MAC prophylaxis start even before ART in severely immunocompromised patients seems problematic, even though prophylaxis cannot prevent MAC IRIS (Phillips 2002+2005). Still, prospective clinical studies have yet to prove whether administration of IL-2 or GM-CSF is worthwhile, as was recently postulated (Pires 2005).
Mycobacterioses in particular should be treated generously with steroids. This has been confirmed in a randomized trial (Meintjes 2010). One should always be prepared for atypical localizations, findings and disease courses of opportunistic infections. Generally speaking, prognosis of IRIS usually is good. Mortality of patients developing IRIS is reportedly not higher than that of patients without IRIS (Park 2006).
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