The immune reconstitution inflammatory syndrome.

A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy in HIV-infected patients is defined as immune reconstitution inflammatory syndrome (IRIS). Because of wide variation in clinical presentation and the still increasing spectrum of symptoms and etiologies reported, diagnosis remains problematic. Furthermore, no test is currently available to establish an IRIS diagnosis. Until a greater understanding of the syndrome is achieved in different regions of the world, clinicians need to remain vigilant when initiating ART and individualize therapy according to known treatment options for the specific infectious agent.

Introduction

A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy (ART) therapy in HIV-infected patients resulting from restored immunity to specific infectious or non-infectious antigens is defined as immune reconstitution inflammatory syndrome (IRIS).

Because clinical deterioration occurs during immune recovery, this phenomenon has been described as immune restoration disease (IRD), immune reconstitution syndrome (IRS), and paradoxical reactions. Given the role of the host inflammatory response in this syndrome, the term (IRIS) has been proposed[1] and has become the most widely used and accepted term to describe the clinical entity.

Etiopathogenesis of IRIS

Despite numerous descriptions of the manifestations of IRIS, its pathogenesis remains largely speculative. Current theories concerning the pathogenesis of the syndrome involve a combination of (1) underlying antigenic burden, (2) degree of immune restoration following Highly active antiretroviral therapy (HAART), and (3) host genetic susceptibility.[2]

Whether elicited by an infectious or noninfectious agent, the presence of an antigenic stimulus for development of the syndrome appears necessary. This antigenic stimulus can be intact, “clinically silent” organisms or dead or dying organisms and their residual antigens. IRIS that occurs as a result of “unmasking” of clinically silent infection is characterized by atypical exuberant inflammation and/or an accelerated clinical presentation suggesting a restoration of antigen-specific immunity.

In noninfectious causes of IRIS, autoimmunity to innate antigens plays a likely role in the syndrome. Possible infectious and noninfectious etiologies of IRIS are summarized in Table 1.[23]

Table 1

Etiology of immune reconstitution inflammatory syndrome

The mechanism receiving the most attention involves the theory that the syndrome is precipitated by the degree of immune restoration following ART. An alternative immunological mechanism may involve qualitative changes in lymphocyte function or lymphocyte phenotypic expression. For instance, following ART an increase in memory CD4+ cell types is observed possibly as a result of redistribution from peripheral lymphoid tissue. This CD4+ phenotype is primed to recognize previous antigenic stimuli, and thus may be responsible for manifestations of IRIS seen soon after ART initiation. After this redistribution, naïve T cells increase and are thought to be responsible for the later quantitative increase in CD4+ cell counts.[4] Thus IRIS may be due to a combination of both quantitative restoration of immunity as well as qualitative function and phenotypic expression observed soon after the initiation of ART.

The third purported pathogenic mechanism for IRIS involves host genetic susceptibility to an exuberant immune response to the infectious or noninfectious antigenic stimulus upon immune restoration. Although evidence is limited, carriage of specific HLA alleles suggests associations with the development of IRIS and specific pathogens.[5]

Diagnostic Criteria for IRIS

French et al., have laid down criteria so as to aid the diagnosis.[6] These are:

Major criteria

Atypical presentation of “opportunistic infections (OI) or tumors” in patients responding to antiretroviral therapy.

Decrease in plasma HIV RNA level by at least 1 log10copies/mL.

Minor criteria

Increased blood CD4+ T-cell count after HAART.

Increase in immune response specific to the relevant pathogen, e.g. DTH response to mycobacterial antigens.

Spontaneous resolution of disease without specific antimicrobial therapy or tumor chemotherapy with continuation of antiretroviral therapy.

Epidemiology of IRIS

Despite numerous descriptions of the infectious and noninfectious causes of IRIS, the overall incidence of the syndrome itself remains largely unknown. In a large retrospective analysis examining all forms of IRIS, 33/132 (25%) of patients exhibited one or more disease episodes after initiation of ART.[7] Other cohort analyses examining all manifestations of IRIS estimate that 17–23% of patients initiating ART will develop the syndrome.[8]

Risk factors identified for the developments of IRIS include:[2]

Male sex

Younger age

Lower CD4+ cell count at ART initiation

Higher HIV RNA at ART initiation

Lower CD4+ cell percentage at ART initiation

Lower CD4+:CD8+ ratio at ART initiation

More rapid initial fall in HIV RNA on ART

Antiretroviral naïve at time of OI diagnosis

Shorter interval between OI therapy initiation and ART initiation

Disease Specific IRIS and Its Management

Mycobacterium tuberculosis IRIS

Mycobacterium tuberculosis (TB) is among the most frequently reported pathogen associated with IRIS. In most studies, TB-IRIS occurs within 2 months of ART initiation.[9] In resource limited developing countries like India it was reported to be 8% in 2007. The incidence of IRIS is expected to rise in this patients group because of the wide availability of HAART in India now.[10]

The most common clinical manifestations of TB-IRIS are fever, lymphadenopathy, and worsening respiratory symptoms. New pulmonary infiltrates, mediastinal lymphadenopathy, and pleural effusions are also common. Extra pulmonary presentations are also possible, including disseminated tuberculosis with associated acute renal failure, intracranial tuberculomas, tuberculous meningitis, skin or visceral abscesses, osteomyelitis, epididymo-orchitis, abdominal TB-IRIS with nonspecific abdominal pain, psoas abscess, bowel perforation, and obstructive jaundice.[3] TB-associated CNS IRIS has also been reported in HIV-positive patients. Compared to non-CNS TB-IRIS, symptoms tend to occur later, usually 5–10 months after ART initiation.[9] Pulmonary TB-IRIS can be diagnosed by transient worsening of chest radiographs, especially if old radiographs are available for comparison.

Treatment for mycobacterial-associated IRIS depends on the presentation and disease severity. Most patients present with non-life-threatening presentations respond to the institution of appropriate antituberculous therapy. However, a range of life threatening presentations, such as acute renal failure, tracheal compression due to lymphadenopathy, refractory or debilitating lymphadenitis, and acute respiratory distress syndrome (ARDS) require systemic corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDS), since the pathogenesis of the syndrome is an inflammatory one, it is reasonable to administer corticosteroids. Interruption of ART is rarely necessary but could be considered in life-threatening situations.

BHIVA has issued guidelines[11] for starting the TB treatment with HAART. If CD4+ count is less than 100 cells/μl, both anti-tuberculosis drugs and HAART can be started together. If CD4+ cells are in the range of 100-200; HAART is started 2 months after starting TB treatment. If the CD4+ cells are above 200, HAART is started 6 months after completing TB treatment.

Atypical mycobacterial IRIS

In addition to TB, atypical mycobacteria are also frequently reported as causative pathogens in IRIS. MAC remains the most frequently reported atypical mycobacterium. In general, MAC-associated IRIS typically presents with lymphadenitis, with or without abscess formation and suppuration.[12]

Treatment is similar to TB-IRIS. Occasionally, surgical excision of profoundly enlarged nodes or debridement of necrotic areas is anecdotally reported. Needle aspiration is another option for enlarged, fluctuant, and symptomatic nodes.

Cytomegalovirus infection

CMV retinitis may be seen either in patients with a prior history of CMV retinitis or in patients with no previous evidence of retinitis. It is speculated that an HAART-induced inflammatory response may be responsible for unmasking a subclinical infection.

In addition to classical CMV retinitis, ART led to new clinical manifestations of the infection, termed immune recovery vitritis (IRV) and immune recovery uveitis (IRU), seen exclusively in people with previous CMV retinitis infection who responded to ARV therapy.

IRV typically will present with acute onset of blurred vision and “floaters” caused by posterior segment inflammation. Ophthalmologic examination reveals numerous inflammatory cells in the vitreous humor. Symptoms usually resolve in one month without specific treatment and without any lasting visual effects.

IRU may occur within months of ART initiation, but typically is a late complication; occurring about 3 years after patients begin ART. It often results in macular edema, epiretinal membrane formation, and/or cataracts, which can lead to permanent vision loss and hence requires a high index of suspicion.[13]

Treatment of IRIS-associated CMV retinitis and IRV involve anti-CMV therapy with gancyclovir or valgancyclovir. However, IRU may not respond to anti-CMV therapy. The use of systemic corticosteroids has been successful, and IRV may require periocular corticosteroid injections.[14]

Varicella zoster virus infection

With the introduction of protease inhibitors, increasing rates of herpes zoster were noted in HIV-infected patients. Incidence rates are three to five times higher than the observed in the pre-HAART era. Mean onset of disease from ART initiation was 5 weeks (range 1–17 weeks).[15]

Although complications such as encephalitis, myelitis, cranial and peripheral nerve palsies, and acute retinal necrosis can occur in immunocompromised HIV patients, the vast majority of patients exhibit typical or atypical dermatomal involvement without dissemination or systemic symptoms.

Cryptococcus neoformans infection

Accurate incidence of C. neoformans-associated IRIS is unknown. The majority of cryptococcal IRIS cases represent reactivation of previously treated cases, suggesting either an immunological reaction to incompletely treated disease or an inflammatory reaction to residual antigens.

C. neoformans-induced IRIS meningitis symptoms range in onset from 7 days to 10 months after initiation of ART, with 20 (49%) occurring within four weeks of therapy. However, C. neoformans-related IRIS patients exhibited had higher baseline plasma HIV RNA levels and higher CSF cryptococcal antigen titers, opening pressures, WBC counts, and glucose levels.[16]

Treatment includes antifungal therapy given in three phases; the induction phase for 14 days with amphotericin B, the consolidation phase with fluconazole for 8 weeks and finally suppressive phase with maintenance dose of fluconazole.[17] During induction phase, amphotericin B is given IV in the doses of 0.7 mg/kg/day and 5 Flucytocin given orally 100 mg/kg/day. After 14 days in the consolidation phase, fluconazole is given orally 400 mg/day for 8 weeks. It is expected that in 8 weeks of fluconazole therapy, the CSF would be sterile, if not the treatment is continued until the CSF is sterile after which maintenance therapy starts with 200 mg of fluconazole/day for life.

It is reasonable to administer systemic corticosteroids to alleviate unresponsive inflammatory effects, as anecdotal benefits have been observed in these patients.[16] Although continuation of ART has been performed safely, interruption of antiviral therapy may be necessary in severe or unresponsive cases.

Pneumocystis jiroveci pneumonia

Immune reconstitution inflammatory syndrome may present as worsening pulmonary symptoms and high fever in patients who had been improving on PCP therapy or in patients with recent successful treatment of PCP. Chest X-ray may show worsening lung involvement and oxygen saturation or arterial blood gas measurements may show worsening hypoxia or alveolar-arterial oxygen gradient. PCP IRIS, in certain cases, may lead to fatal acute respiratory failure.[18]

Summary

While exact estimates of incidence are not yet available, IRIS in patients initiating ART has been firmly established as a significant problem in both high and low income countries. Because of wide variation in clinical presentation and the still increasing spectrum of symptoms and etiologies reported, diagnosis remains problematic. Furthermore, no test is currently available to establish an IRIS diagnosis.

Diagnosis of IRIS requires a high index of suspicion. Detailed clinical history should be taken in patients suspected to have IRIS, which includes the following symptoms:

Fever, cough or any specific symptoms; history of OIs: including recently diagnosed as well as past OIs; treatment of OIs: date of initiation, duration of therapy, clinical response, adherence, defaulter, resistance; ART initiation: date, regimen, adherence, prior history of ART, toxicity, any drug interaction; CD4+ count and HIV viral load prior to ART initiation.

Look for the vital signs, including temperature, heart rate, blood pressure, and respiratory rate. Perform a careful and thorough physical examination based on symptoms and suspicion of systems involved. Ophthalmologic examination should be included in all patients.

The following investigations should be considered before starting ART: complete blood count with differential, ESR, serum electrolytes, liver function tests and renal function tests, CD4+ count and HIV viral load, chest X-ray, Mantoux (tuberculin) test, sputum stain and culture, and ultrasonography of abdomen. In a suspected case, even an initially negative Mantoux test becoming positive could be suggestive of IRIS.

Patients who are started on ART having CD4+ count of less than 100 cells/μl require close clinical monitoring during the first weeks of ART. Similarly, they should be counseled about the risk of development of IRIS to avoid being discouraged and defaulting on therapy as development of IRIS suggests increase in the immunity and is a good sign unless life threatening.

Failure of ART can be ruled out with the decrease in CD4+ count, increase in viral load, along with clinical deterioration while active opportunistic infections can be ruled out by isolating the pathogens. The World Health Organization (WHO) made an important distinction between IRIS and clinical failure while on anti-HIV therapy.[19]

“Clinical failure is defined as clinical disease progression with development of an opportunistic infection or malignancy when the drugs have been given sufficient time to induce a protective degree of immune restoration. This needs to be differentiated from an immune reconstitution syndrome which can be seen within the first several weeks after the institution of therapy if a subclinical infection is present at baseline.”[19]

Treatment of IRIS will remain a clinical challenge due to the variety of clinical presentations and the presence of multiple pathogens capable of causing the syndrome. Until a greater understanding of the syndrome is achieved in different regions of the world, clinicians need to remain vigilant when initiating ART and individualize therapy according to known treatment options for the specific infectious agent.