What is Immune Reconstitution Inflammatory Syndrome?
Human immunodeficiency virus, or HIV, attacks the body’s immune system by reducing a specific type of cell, called CD4+ T lymphocytes, that help our bodies fight infections. This reduction leaves people with HIV more susceptible to other dangerous infections. A treatment method called Highly Active Antiretroviral Therapy (HAART) helps to restore these essential cells and boost the immune system, helping patients fight off harmful germs. As a result, patients using HAART have seen significant improvements in their overall health and quality of life.
While HAART has been a crucial development in reducing deaths related to HIV, there are still some challenges associated with this form of therapy. Some people have reported various side effects arising from HAART, ranging from mild to severe allergic reactions, unique individual reactions, blood disorders, and changes in how the body processes drugs. Additionally, HAART can increase the levels of certain medications in the bloodstream due to drug interactions, which can lead to other significant side effects.
A significant complication that can happen with HAART therapy is a health condition known as the immune reconstitution inflammatory syndrome (IRIS). Currently, the exact workings of IRIS are not fully understood. IRIS involves an excessive and unregulated immune response against opportunistic infections and typically emerges in the first six months of treating HIV/AIDS patients using HAART. First reported in the 1990s, IRIS can affect patient adherence to HAART, increase the risk of drug resistance, worsen HIV progression to AIDS, and diminish the quality of life in infected individuals. In summary, IRIS is linked with serious health impacts and potential death in HIV/AIDS patients.
This piece offers a comprehensive look at the risk factors, workings, associated germs, symptoms, and treatment of IRIS in HIV patients starting HAART.
What Causes Immune Reconstitution Inflammatory Syndrome?
Immune reconstitution inflammatory syndrome (IRIS) is a medical condition that was first discovered in the 1980s. It occurred in patients suffering from tuberculosis and leprosy who were undergoing treatment. Doctors noticed that these patients, after starting their treatment, began to unexpectedly worsen in their symptoms. Some of these symptoms included increased fever, weight loss, fatigue, and trouble breathing for tuberculosis patients. Patients with leprosy saw worsening skin sores. At that time, it was unclear why this was happening, but it was later determined that this was due to an unusual switch from an anti-inflammatory condition in untreated patients to a pro-inflammatory condition once treatment began. These days, IRIS is commonly linked with HIV treatment; however, it can also occur in situations not related to HIV.
Here are some non-HIV-related situations where IRIS has been observed:
1. Solid Organ Transplant Recipients: People who have undergone solid organ transplants, like liver and kidney transplants, are put on medicine to suppress their immune system, like tacrolimus or cyclosporine which aim to control the immune response. IRIS symptoms in these patients are believed to be a result of an anti-inflammatory response seen after these medicines are stopped.
2. After childbirth: Pregnancy is a time when the immune system is slightly weakened. The body, during pregnancy, switches to anti-inflammatory responses to prevent any rejection of the fetus or miscarriage. However, after childbirth, this process is reversed. This change can result in a pro-inflammatory state immediately after birth, which increases the risk of IRIS.
3. Neutropenic Patients: These are patients with a very low count of a particular type of white blood cell called neutrophils. As a result, these individuals are at higher risk of opportunistic fungal and viral infections. However, these infections may not show symptoms until the neutrophil counts increase, thus presenting as IRIS.
4. Patients on Tumor Necrosis Factor Antagonists (TNF antagonists): Medicines such as infliximab, adalimumab, and others are used to treat chronic inflammation, found in conditions like ulcerative colitis or Crohn’s disease. These medicines can significantly impair the body’s response against infections such as TB (tuberculosis). These TB infections can remain hidden while using TNF antagonists, but once the medication is stopped, there is activation that can lead to IRIS.
Risk Factors and Frequency for Immune Reconstitution Inflammatory Syndrome
Ever since the first HAART drug, zidovudine, was introduced in 1987 and combination therapy began in 1996, there has been a marked decrease in cases of HIV-related infections. Numerous studies have shown that HAART therapy significantly improves survival rates for people with HIV/AIDS. This approach to treatment has improved health outcomes for HIV patients, including reducing the number of deaths among them.
HAART has several key benefits when used in the treatment of HIV/AIDS:
- It reduces the amount of HIV virus in the body.
- Leads to the increase in CD4+ T cells, which help fight infections.
- It restores the immune system’s ability to protect against infections.
However, it also has potential side effects:
- HAART drugs can cause nausea, lethargy, cold, loss of taste sensation, anxiety, anorexia, depression, and nerve pain in the hands and feet. They may also cause more other issues such as anemia, pancreatitis, and liver toxicity.
- Immune Reconstitution Syndrome (IRIS) can occur in up to a third of HIV patients starting on HAART. It is a severe response against dormant infections that occurs after the immune system has improved due to therapy.
- The risk of drug interactions increases. Interactions can occur between HAART and drugs used to treat other conditions in patients with HIV/AIDS.
For instance, certain combinations of drugs can lead to an increase in drug-related side effects, such as increased risk of liver and blood toxicity, kidney toxicity and respiratory depression. Also, certain combinations of drugs can decrease the efficacy of one or the other drug, and there are combinations that increase the risk of heart arrhythmia and organ toxicity.
The prevalence of IRIS is anticipated to rise given the growing use of HAART among HIV patients. Some estimates suggest that 25% to 30% of HIV patients on antiretroviral therapy experience IRIS. We don’t yet know how often IRIS occurs in non-HIV patients such as those with a weakened immune system, just after childbirth, taking medications to reduce inflammation or after organ transplant surgery.
There are certain risk factors associated with a higher likelihood of developing IRIS in non-HIV patients, although they are not fully understood. Similar to HIV patients, a sudden shift from a state of low inflammation to high inflammation could potentially increase the risk for IRIS, such as in patients taking certain medications or recovering from specific treatments.
In HIV patients, the following factors can increase the risk of IRIS:
- Starting HAART treatment at a younger age or in male patients.
- Having a CD4+T cell count less than 100 cells per microliter when starting HAART.
- Seeing a rapid increase in the CD4 count after starting HAART.
- Experiencing a rapid decrease in HIV RNA viral levels within ninety days of starting HAART signals an increased risk.
- Having a latent opportunistic infection with a high burden of antigens.
- Starting HAART soon after (within 30 days) completing treatment for an opportunistic infection.
Research also suggests that genetics could play a part in who is at an increased risk for IRIS.
Signs and Symptoms of Immune Reconstitution Inflammatory Syndrome
In patients suffering from HIV/AIDS, opportunistic infections like Mycobacterium, fungi, viruses, and parasites can cause silent or slow infections due to a weakened immune system. Patients might not show any symptoms until they start treatment called HAART, which revitalizes the immune system. This revitalization can sometimes result in an overly intense immune response. This phenomenon is known as Immune Reconstitution Inflammatory Syndrome, or IRIS. The symptoms of IRIS vary depending on the part of the body affected and the severity of the immune response.
When it comes to diagnosing IRIS, there is no universal agreement in the medical community. However, there are usual criteria to be met for someone to be diagnosed with IRIS:
- The patient should test positive for HIV.
- The patient should be taking HAART treatment, and show a decrease in the level of HIV-1 RNA and/or an increase in CD4+ cells.
- The patient should exhibit symptoms of an inflammation.
- The patient’s condition shouldn’t be due to previously diagnosed or newly diagnosed OIs (Opportunistic Infections) or side effects from medication.
IRIS can cause different symptoms based on the infecting organism. Here are some of the most common symptoms related to specific organisms:
- Mycobacterium Tuberculosis: coughing, shortness of breath, swollen lymph nodes, skin lesions, fever, chills, weight loss, and night sweats.
- Mycobacterium Avium Complex: swollen lymph nodes.
- Cryptococcus Neoformans: confusion, seizures, increased intracranial pressure, coughing, and shortness of breath.
- Cytomegalo Virus (CMV): blurred vision, decreased vision sharpness, ocular pain, shortness of breath due to pneumonia, and diarrhea from CMV colitis.
- Pneumocystis Jirovecii: fever, chills, general discomfort, weight loss, coughing, and shortness of breath.
- JC Virus: confusions, visual symptoms such as double vision and blindness, or imbalance while walking due to a potentially life-threatening condition called PML.
- Hepatitis B and C Viruses: fever, chills, loss of appetite, weight loss, nausea, and jaundice.
- Kaposi Sarcoma: worsening skin and mucosal lesions with increased swelling and tenderness, peripheral swelling.
- Herpes Zoster: skin and eye lesions.
Testing for Immune Reconstitution Inflammatory Syndrome
When a person is being evaluated for Immune Reconstitution Inflammatory Syndrome (IRIS) – a condition where an already infected individual experiences a sudden worsening of symptoms after starting treatment – the healthcare provider may suspect different microorganisms as the original source of infection. Depending on the suspected culprit, different tests may be conducted:
1. Mycobacterium tuberculosis: In this case, a chest X-ray might show new lung issues or fluid build-up, and measures of inflammation in the body, like the erythrocyte sedimentation rate or C-reactive protein, may be elevated. Also, a fine needle may be used to extract a sample from swollen and sore lymph nodes, which could reveal a “cold abscess” – an abscess that does not contain any actively growing bacteria or other microorganisms. Initially, a skin test for tuberculosis might turn out negative but can later become positive.
2. Mycobacterium avium complex: As with tuberculosis, a needle sample taken from the swollen and sore lymph nodes may provide useful insight. In this case, well-formed granulomas – inflammatory nodules – may be spotted under the microscope.
3. Cryptococcus neoformans: If this fungus is suspected, X-rays might show new cavities in the lungs if there was a prior infection. If the brain or spinal cord are affected, a lumbar puncture – where a thin needle is used to draw out spinal fluid – can show elevated pressure and elevated white blood cell count
4. Pneumocystis jirovecii: In this case, chest X-rays will often show a certain pattern of lung infiltration. This diagnosis can also be confirmed by a procedure called bronchoscopy, where a small tube is used to examine the airways and extract samples.
5. Cytomegalovirus: In scenarios where it causes inflammation and cell death in the retina – a condition known as “immune recovery uveitis”- an examination of the back of the eye can confirm the diagnosis.
6. JC virus: If this virus is suspected, magnetic resonance imaging (MRI) may show lesions – areas of tissue damage – in the brain’s white matter. A lumbar puncture or brain biopsy can also help to confirm the diagnosis.
7. Herpes zoster: This condition is often diagnosed clinically based on the characteristic painful skin rashes that follow the path of certain nerves in the body.
8. Hepatitis B and C viruses: If these viruses are suspected, certain blood tests can help to diagnose the condition. For example, an increase in protective antibodies or a change from a previous negative test to a positive one can suggest Hepatitis. Also, a liver biopsy – where a small sample of liver is removed for examination – can show cell death and inflammation.
9. Kaposi sarcoma: Diagnosis is usually based on the appearance of skin and mucosal lesions – abnormal patches of tissue.
Preventing the onset of IRIS in HIV patients can be achieved through screening for latent infections before starting antiretroviral therapy. In addition, patients at high risk of severe IRIS can be given steroids to minimize the risk and severity of symptoms.
Treatment Options for Immune Reconstitution Inflammatory Syndrome
When dealing with immune reconstitution inflammatory syndrome (IRIS), a condition where the immune system causes inflammation as it begins to recover, it’s important to focus on managing symptoms. Part of this treatment involves using antibiotics or other drugs to treat the infection that triggered the syndrome.
It’s also recommended to continue with HIV treatment, known as highly active antiretroviral therapy (HAART), unless it’s causing severe side effects or if IRIS is affecting the brain and spinal cord. Usually, HAART should be started within two weeks of diagnosing most infections that occur when the immune system is weak. However, if the infection is in the brain (for example, meningitis caused by the fungi Cryptococcus or tuberculosis), starting HAART might be delayed to reduce the risk of a severe IRIS reaction in the brain.
Management of IRIS also involves keeping the patient hydrated, correcting any electrolyte imbalances, and improving nutritional status. Mild symptoms like fever and pain can be managed with over-the-counter drugs like paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs).
For patients with severe lung disease leading to low oxygen levels in the blood (like pneumonia caused by the fungus Pneumocystis jirovecii) or brain inflammation caused by Cryptococcus, steroids can be helpful. If patients with severe IRIS in the brain do not respond to steroids, biological drugs that block TNF-alpha, a substance that stimulates inflammation, can be used. For patients with IRIS triggered by cytomegalovirus (CMV), a common virus that can cause eye disease in people with weakened immune systems, steroids can be injected into the eye to reduce inflammation.
What else can Immune Reconstitution Inflammatory Syndrome be?
Immune reconstitution inflammatory syndrome, or IRIS, can display a range of different symptoms and might be hard to diagnose. There are several conditions that resemble IRIS very closely, so these need to be checked for and ruled out before a final diagnosis of IRIS can be made. These conditions include:
- Side effects from HAART therapy or anti-microbial treatments.
- Resistance to anti-microbial drugs and a subsequent advancement of opportunistic infections (OI) as a result.
- Failure to take anti-microbial drugs consistently leading to an escalation in existing OI.
- New, untreated opportunistic infections.
What to expect with Immune Reconstitution Inflammatory Syndrome
Most instances of immune reconstitution inflammatory syndrome – a condition where an improving immune system triggers inflammation – are mild and tend to get better on their own. However, in severe cases where this syndrome affects the central nervous system (which includes the brain and spinal cord) or the lungs, it could potentially result in death or lasting damage.
Possible Complications When Diagnosed with Immune Reconstitution Inflammatory Syndrome
Detecting and treating IRIS promptly is crucial because severe IRIS can lead to serious complications such as:
- Death due to severe breathing problems caused by low levels of oxygen (acute hypoxic respiratory failure) and complications in the central nervous system, in cases related to TB-IRS and Cryptococcus-IRS.
- A potentially fatal brain disease that causes damage to the protective layer of nerve cells (progressive multifocal leukoencephalopathy or PML). This is due to the JC virus-associated IRS.
- Certain types of cancer, such as Kaposi sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma, being linked to IRIS.
- Permanent loss of vision in severe cases of CMV keratitis, an inflammatory eye condition.
Hence, it’s essential to identify IRIS and treat it in a timely manner to prevent these serious complications.
