Continuing Education Activity

Immune reconstitution inflammatory syndrome (IRIS) is a state of hyperinflammatory response that usually occurs in the first six months of treatment of HIV/AIDS patients. It is a potential complication of the use of highly active antiretroviral therapy (HAART). The overall incidence of IRIS is still unknown. However, some studies report that up to 25 to 30% of HIV patients who are on antiretroviral therapy have IRIS. This activity outlines the risk factors, pathophysiology, clinical presentation, and the role of the interprofessional team in the management of immune reconstitution syndrome.

Objectives:

• Summarize the prevalence of immune reconstitution inflammatory syndrome in HIV/AIDS patients that are initiated on HAART.
• Review the risk factors that have been associated with an increased risk of immune reconstitution inflammatory syndrome while being treated with HAART.
• Identify the common clinical presentation associated with immune reconstitution inflammatory syndrome.
• Outline some interprofessional team strategies that can be used to improve patient outcomes for individuals who present with immune reconstitution inflammatory syndrome.

Introduction

Human immunodeficiency virus (HIV) targets the immune system by depleting CD4+ T lymphocytes and predisposing patients to an increased risk of opportunistic infections. The use of the highly active antiretroviral therapy (HAART) leads to the restoration of CD4+ T lymphocytes and the normalization of an immune response against pathogens.[1][2] This improvement in immunity has resulted in significant improvement in the quality of life and health care outcomes in HIV patients.[3] 

Although the introduction of HAART has been a landmark in preventing HIV-related deaths, there are still issues with HAART therapy. Since its inception, there have been several reported side effects of HAART and its possible interactions with other medications. Side effects can range from mild-severe allergic reactions, idiosyncratic reactions, hematological disorders to altered drug metabolism.[4][5] Additionally, using HAART therapy, the serum levels of certain medications can increase due to drug interaction causing significant side effects.[6]

Another potential complication that may arise with HAART therapy is immune reconstitution inflammatory syndrome (IRIS). IRIS is a poorly understood disease, and its exact mechanism is not yet fully known. It is a state of dysregulated, hyper-inflammatory response against opportunistic infections that usually occurs in the first six months of treatment of HIV/AIDS patients.[7][8][9] IRIS is a potential complication of highly active antiretroviral therapy (HAART) and was first reported in the 1990s. It can lead to poor adherence and compliance with HAART in HIV/AIDS patients.[10][11][12] It can also increase the risk of drug resistance with HAART, worsen HIV progression to AIDS, and decrease the quality of life in HIV infected population. Overall, the IRIS has been associated with significant morbidity and mortality in HIV/ AIDS patients. This article provides a comprehensive review of the risk factors, pathophysiology, associated microorganisms, clinical presentations, and treatment of IRIS in HIV patients following the initiation of HAART.

Etiology

The Historical Aspects of the IRIS

Immune reconstitution inflammatory syndrome (IRIS) was first discovered in the 1980s in patients with tuberculosis and Leprosy who were receiving treatment. Physicians at that time noted a paradoxical worsening of fever, weight loss, fatigue, and shortness of breath in patients with pulmonary TB and worsening of skin lesions in patients with Leprosy after initiation of treatment.[13][14][15] The mechanism for this was not clear at that time. Still, it was later attributed to a shift from a relative anti-inflammatory state in untreated TB and Leprosy to a pro-inflammatory state that occurs once the immune system recovers after initiation of treatment. Following the HIV/AIDS epidemic in the 1980s, and with HAART therapy initiation, IRIS is now a phenomenon that is most commonly associated with HIV treatment. It can, however, occur in conditions or scenarios that are not HIV-related.

The following are non-HIV related conditions where IRIS has been observed:[16]

1. Solid Organ Transplant Recipients

Solid organ transplant recipients (e.g., liver, kidney transplants) are placed on immunosuppressive agents such as tacrolimus or cyclosporine. These agents target CD4 positive cells and suppress their functioning. IRIS seen in solid organ transplant recipients is thought to be secondary to the antiinflammatory response seen after withdrawal of these immunosuppressive agents. Cryptococcosis, Cytomegalovirus disease, and tuberculosis are the most common infections associated with IRIS in solid organ transplant recipients.

2. Postpartum Period 

Pregnancy is a period of the relatively immunocompromised state.  During pregnancy, there is a shift to the activation of Th2 cells and an increased IL-4, IL-5, and IL-10. There is also a suppression of Th1 cells and associated cytokines (IL-12, TNF-a). This results in a state of anti-inflammatory response, needed during pregnancy to prevent any fetal rejections or miscarriages. However, after pregnancy, there is a reversal of this process and results in a relative pro-inflammatory state immediately postpartum. Thus, the immediate postpartum period (3 to 6 weeks) has an increased risk of IRIS, most commonly with cryptococcosis, herpes virus infection, human papillomavirus reactivation, leprosy, tuberculosis, viral hepatitis, and a flare-up of autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis.

3. Neutropenic Patients

Patients with an absolute neutrophil count (ANC) below 500 per microliter are at increased risk of fungal and viral opportunistic infections (Aspergillus infections, CMV). These infections might initially be latent or have subacute presentations but become clinically apparent only after the neutrophil counts improve, thus, presenting as IRIS. Most commonly observed IRIS in neutropenic patients has been associated with invasive pulmonary aspergillosis and chronic disseminated candidiasis.

4. Patients on Tumor Necrosis Factor Antagonists (TNF antagonists)

TNF antagonists such as infliximab, adalimumab, certolizumab, and etanercept are used to treat chronic inflammatory conditions such as ulcerative colitis, Chrohn disease, or sarcoidosis. Tumor necrosis factors play an integral role in macrophage activation and granuloma formation. Thus, the use of TNF antagonists can significantly impair the host response against infections such as TB. These TB infections can be latent while using TNF antagonists, but once these medications are discontinued, there will be a subsequent macrophage activation, leading to IRIS associated with TB.

Epidemiology

Since the introduction of the first HAART drug, zidovudine, in 1987 and the initiation of combination therapy in 1996, there has been a significant decrease in the incidence of HIV-related opportunistic infections. Several studies have demonstrated clear mortality benefits of HAART therapy in HIV/ AIDS. Its inception has led to the dramatic improvement in HIV-related outcomes, including mortality outcomes in HIV patients.

The use of HAART in HIV/AIDS provides the following benefits:

1. It decreases HIV viral load. 
2. It leads to an increase in CD4+ T lymphocytes.
3. It restores protective humoral and cellular immune functions against infections. 

The potential adverse outcomes from the use of HAART are outlined below:

A. Side effects of HAART drugs: The most frequently encountered adverse effect of HAART includes nausea, lethargy, cold, loss of taste sensation, anxiety, anorexia, depression, peripheral neuropathy. Other potential side-effects include anemia, lactic acidosis, pancreatitis, hepatotoxicity, lipodystrophy, specifically noted with nucleoside reverse transcriptase inhibitors (NRTI), Non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PIs) use. Prior studies have reported that HAART related side effects have resulted in medication non-compliance, which has led to drug resistance, progression to AIDS, and increased mortality.[17] 

B. Immune reconstitution syndrome (IRIS): IRIS is a potential complication of initiation of HAART. It can occur in up to a third of cases of HIV patients initiated on HAART. It is a state of hyper-inflammatory response against latent infections that happens after the improvement in CD4 cell count and immune response once therapy for HIV has started. Commonly reported opportunistic pathogen is cytomegalovirus, mycobacterium, cryptococcus, Epstein-Barr virus, pneumocystis, JC virus, hepatitis B, and C. Therefore, the knowledge of any latent infections in patients is crucial before starting HAART in HIV/AIDS patients. The clinical presentation and severity of IRIS depend on the organism involved, location of the infection, and severity of inflammatory response.[7][8][9]

C. The risk for drug-drug interactions:  Drug-drug interactions can occur between HAART and drugs used for treating other conditions in patients with HIV/AIDS. The most commonly encountered drug interactions in HIV/AIDS patients treated with HAART drugs occur in patients receiving treatment for cancer and patients receiving treatment for other co-infections like tuberculosis, fungal infections. Drugs metabolized by the cytochrome P450 enzyme system includes NNRTI, PIs, anti-tubercular, anti-cancer drugs. These drugs interact with each other either by inducing or inhibiting the efficacy of one another.[18] The common mechanism of drug-drug interactions and examples are as follows:[19] 

Increase in Serum Level of Drugs and Increased Risk of Drug-related Side-effects

• The use of fluconazole and zidovudine (ZDV) can increase the serum concentration of ZDV and lead to an increased risk of hepatotoxicity and hemato-toxicity.
• NSAID use with efavirenz (EFV) can increase serum concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) and cause an increase in the risk of nephrotoxicity.
• Co-administration of morphine and EFV increases the serum concentration of morphine, resulting in respiratory depression.

Decreased Serum Level of Drugs and Decreased Therapeutic Efficacy

• Use of anti-epileptics such as carbamazepine can decrease the levels of NNRTI (non-nucleoside reverse transcriptase inhibitor)
• Rifampicin for treatment of TB can decrease serum concentrations of efavirenz (EFV) and zidovudine (ZDV)

QTc Prolongation and Increased Risk of Arrhythmia

• Use of haloperidol with protease inhibitors (PI) or azithromycin with ZDV can lead to an increase in QTc and result in cardiac arrhythmias.

Increased Risk of Organ Toxicity

• Simultaneous use of nitrofurantoin and ZDV can increase myelosuppression associated with both agents.
• The combination of isoniazid and stavudine can increase the risk of neuropathy associated with isoniazid.

The prevalence of IRIS is likely to increase with the increasing use of HAART in HIV patients. Some studies reported that up to 25% to 30% of HIV patients on antiretroviral therapy have IRIS.[20][21] The prevalence of IRIS in non-HIV patients such as neutropenic patients, women in the post-partum period, patients on TNF-alpha blockers, or solid organ transplant recipients on immunosuppressive therapy is not known. 

Risk factors for IRIS

The risk factors for IRIS in non-HIV patients are not fully understood. However, similar to HIV patients, an abrupt shift from an anti-inflammatory state to a pro-inflammatory state would cause an increased risk for IRIS. For example, patients on TNF-alpha blocking agents or high doses of steroids, abruptly taken off of medications, or neutropenic patients who have an abrupt improvement in white cell counts following allogeneic bone marrow or stem cell transplantations.[16][22]

In the case of HIV patients receiving HAART based on prior observational studies, the following are the risk factors for IRIS:[23]

1. Starting HAART treatment at a younger age or in male patients has shown an association with an increased risk of developing IRIS.

      2. CD4+T cell count less than 100 cells per microliter at the time of initiating HAART.[24]

      3. An accelerated rise in CD4 count following treatment with HAART.

      4. Rapid HIV RNA viral suppression within ninety days of HAART increases the risk of immune reconstitution syndrome.

      5. Pre-existing latent opportunistic infection with a high antigenic burden increases the risk and severity of IRIS. 

      6. Initiating HAART within a short time interval (30 days) after completing treatment for opportunistic infection.       

      7. Studies have also suggested that genetics play a role in determining who is at an increased risk for IRIS, particularly in herpes and mycobacterial infections (HLA-A, -B44, -DR4 associated with herpes virus IRIS), and TNFA-308*1, IL6-174*G (associated with mycobacterial IRIS).[21][25]

Pathophysiology

Pathogenesis of IRIS in HIV patients:[26][27][28][29]

Immune reconstitution inflammatory syndrome has been extensively studied in HIV patients receiving HAART. The terms "unmasking," "unregulated," and "paradoxical" are often used to describe the state of hyper-inflammatory response seen with the IRIS. Patients who are HIV positive and have low CD4 positive cell count usually start seeing a decrease in viral load within the first 1 to 2 weeks after initiation of HAART. An improvement in CD4 counts usually occurs in the first three to six months of initiation of HAART.

As mentioned above, having a low CD4 count, and disseminated latent infection prior to initiation of HAART, rapid improvements in CD4 count, suppression of infection after HAART initiation are all risk factors for IRIS. The underlying mechanism of IRIS is complex and is thought to be due to an imbalance between anti-inflammatory cytokines and pro-inflammatory cytokines that occurs rapidly after the recovery of immune function in HIV patients initiated on HAART.

After initiation of HAART, there is an increase in CD4 count. This includes an initial rapid increase in memory CD4 positive T cell counts due to decreased apoptosis and lymphocyte redistribution from peripheral lymphoid tissues. A slower increase follows this in counts of naive CD4 positive T cells. Later during the course of the treatment, there is a clonal proliferation of these CD4 positive cells causing a further increase in cell counts. Along with CD4 positive T cells, there is also improvement in CD8 positive T cells. 

This dramatic improvement in CD4 positive and CD8 positive T cell counts leads to an improvement in cell-mediated and antibody-mediated immunity. And it can lead to the following:

1. An excess pathogen-specific cellular immune response.
2. Decrease in the capacity of regulatory T cells to regulate and suppress inflammation.
3. Uncoupling of both innate and acquired immunity.

All of this culminates in a state of hyperinflammatory response against underlying pathogens, culminating in IRIS symptoms.

History and Physical

Opportunistic pathogens such as Mycobacterium, fungi, viruses, parasites can cause latent or subacute infections in HIV/AIDS patients. Due to an immunodeficient state and lack of inflammatory response, the patient can remain asymptomatic. Following the initiation of HAART, however, there is an anticipated improvement in an immune-mediated inflammatory response. This hyper-inflammatory response is the hallmark of IRIS. The clinical presentation depends on the underlying pathogen and organ/system involved and the severity of the inflammatory response.[30]

There is no universal definition of IRIS and broad consensus on diagnostic criteria, but the following criteria usually need to be met before the diagnosis of the IRIS in HIV positive patients:[31][32]

1. The patient should be HIV-positive.
2. The patient should be receiving HAART with either a decrease in HIV-1 RNA level from baseline or an increase in CD4+ cells from baseline or both. 
3. Clinical symptoms should be consistent with an inflammatory process.
4. Clinical course not consistent with:
   • Expected course of previously diagnosed OI.
   • Expected course of newly diagnosed OI.
   • Drug toxicity or side effects. 

The most common organism-specific clinical manifestations of IRIS are as follows:[20][21][30]

Evaluation

The following table summarizes the investigative approaches for IRIS based on the suspected micro-organism.[11][33][34][35][36]

Approaches to prevent IRIS in HIV patients:[37]

1. Presence of latent or subacute infections with high antigen burden has been associated with the onset and severity of the IRIS. Thus, screening for latent infections, e.g., TB screening with PPD test/Interferon-gamma test, cryptococcal antigen screening for latent cryptococcal infections, should be done in every patient before starting the HAART. 
2. Patients who are at high risk of having severe IRIS, e.g., HIV patients with a known Pneumocystis jirovecii infection, can be started on steroids empirically before or during the initiation of HAART to minimize the risk and severity of IRIS.

Treatment / Management

The management of immune reconstitution inflammatory syndrome should focus on symptom control. It is equally important that the treatment includes the initiation of anti-microbial agents for the underlying opportunistic infection associated with the IRIS. It is also highly recommended to continue HAART unless there is evidence of severe HAART-related toxicity or IRIS with central nervous system (CNS) involvement.[20] The current guidelines recommend initiating HAART within two weeks of diagnosis of most opportunistic infections. However, special consideration must be given to opportunistic infections involving the CNS (e.g., cryptococcal and tubercular meningitis). HAART may be delayed further due to the risk of potentially fatal CNS immune reconstitution inflammatory syndrome.

Supportive management includes hydration, correction of electrolyte abnormalities, and optimization of nutritional status. Mild symptoms of IRIS, such as fever and pain, can be managed with paracetamol or with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with severe lung disease causing acute hypoxic respiratory failure (e.g., pneumonitis secondary to Pneumocystis jirovecii) and CNS disease such as Cryptococcus-related CNS IRIS are likely to benefit from steroid use. For patients with severe CNS-IRIS resistant to steroids, biological agents such as TNF-alpha antagonists can be used. Patients with CMV-IRIS can benefit from Intraocular steroid administration.[37][38][39][40]

Differential Diagnosis

Immune reconstitution inflammatory syndrome has a heterogeneous presentation and can be difficult to diagnose at times. The following conditions can closely mimic the IRIS and must be considered or ruled out before the diagnosis of the IRIS is made.[31][32]

1. Side effects of HAART therapy or anti-microbial treatment. 2. Resistance to anti-microbial agents and progression of opportunistic infections (OI) as a result. 3. Lack of adherence to anti-microbial agents leading to worsening of existing OI. 4. New untreated opportunistic infections.

Prognosis

The majority of cases of immune reconstitution inflammatory syndrome are mild and self-limiting. However, severe IRIS with CNS or pulmonary involvement can potentially lead to death or permanent impairment.[30][41]

Complications

Timely identification and management of IRIS are important as severe IRIS can be associated with complications, as outline below: 

1. TB-IRS and Cryptococcus-IRS can lead to death due to acute hypoxic respiratory failure and CNS complications.[33][34][33]
2. Progressive multifocal leukoencephalopathy (PML) can be a potentially fatal demyelinating CNS disease due to the JC virus-associated IRS.[42]
3. Malignancies such as Kaposi sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma have been associated with the IRIS.[43]
4. Permanent blindness in case of severe CMV keratitis.[44]

Enhancing Healthcare Team Outcomes

Immune reconstitution inflammatory syndrome (IRIS) is a state of a dysregulated and excess immune response against latent or subacute opportunistic infections that can occur in up to one-third of HIV patients following HAART initiation. IRIS can also be seen in non-HIV patients with latent infections such as in females in the post-partum period, patients on TNF-alpha blockers, neutropenic patients with stem cell transplants, and patients with a history of solid organ transplants on immunosuppressants. Its clinical presentation can be heterogeneous and depends on the underlying organism causing the latent infection, location of the infection, and severity of inflammatory response following immune recovery.

The diagnosis of IRIS can be challenging as its clinical presentation can be similar to drug-related side effects or progression of existing opportunistic infections due to lack of adherence or resistance of anti-microbial agents. Timely identification of IRIS can lead to avoidance of complications, which in case of severe CNS-IRIS or pulmonary IRIS, can be life-threatening. Thus, HIV positive patients initiated on HAART need close follow up with an interprofessional team consisting of health care professionals including primary care doctors, infectious disease specialists, pharmacists, and nurses to monitor for symptoms of IRIS and timely initiation of treatment.