Immune Reconstitution Inflammatory Syndrome

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:

1. Solid Organ Transplant Recipients

Solid organ transplant recipients (eg, liver and 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.[16] 

2. Postpartum Period 

Pregnancy is a period of a 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, which is needed during pregnancy to prevent any fetal rejections or miscarriages. However, after pregnancy, this process reverses, which results in a relatively 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. The 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 treat chronic inflammatory conditions such as ulcerative colitis, Crohn disease, or sarcoidosis. Tumor necrosis factors play an integral role in macrophage activation and granuloma formation. Thus, 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 is 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 a 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 effects of HAART include nausea, lethargy, cold, loss of taste sensation, anxiety, anorexia, depression, and peripheral neuropathy. Other potential side effects include anemia, lactic acidosis, pancreatitis, hepatotoxicity, and 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 pathogens are 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, the infection's location, and the inflammatory response's severity.[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 and fungal infections. Drugs metabolized by the cytochrome P450 enzyme system include NNRTI, PIs, anti-tubercular, and 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

• The 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 who are 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 is less than 100 cells per microliter when 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 3 to 6 months of initiation of HAART. As mentioned above, having a low CD4 count and disseminated latent infection before initiating HAART, rapid improvements in CD4 count, and 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 rapidly increasing 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 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 improves cell-mediated and antibody-mediated immunity. 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.

This culminates in a hyperinflammatory response against underlying pathogens, culminating in IRIS symptoms.

History and Physical

Opportunistic pathogens such as Mycobacterium, fungi, viruses, and 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. However, after HAART initiation, an improvement in an immune-mediated inflammatory response is anticipated. 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 or broad consensus on diagnostic criteria. Still, the following criteria usually need to be met before the diagnosis of IRIS in HIV-positive patients:

1. The patient should be HIV-positive.
2. The patient should receive 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.[31][32] 

The most common organism-specific clinical manifestations of IRIS are as follows:

Evaluation

The following table summarizes the investigative approaches for IRIS based on the suspected micro-organism.

Approaches to prevent IRIS in HIV patients:[37]

1. The 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, eg, 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, eg, 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 initiating 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 2 weeks of diagnosing most opportunistic infections. However, special consideration must be given to opportunistic infections involving the CNS (eg, 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, correcting electrolyte abnormalities, and optimizing 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 (eg, 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 resistance 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](A1)

Differential Diagnosis

Immune reconstitution inflammatory syndrome has a heterogeneous presentation and can sometimes be difficult to diagnose. 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 leads to worsening 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 outlined 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, and non-Hodgkin lymphoma have been associated with the IRIS.[43]
4. Permanent blindness in case of severe CMV keratitis.[44]