Immune reconstitution inflammatory syndrome | |
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Specialty | Immunology ![]() |
Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. [1]
IRIS may also be referred to as immune reconstitution syndrome, immune reconstitution disease, immune recovery disease, and immune restoration disease. [2]
Systemic or local inflammatory responses may occur with improvement in immune function. While this inflammatory reaction is usually self-limited, there is risk of long-term symptoms and death, particularly when the central nervous system is involved. [3] [4]
Management generally involves symptom control and treatment of the underlying infection. In severe cases of IRIS, corticosteroids are commonly used. Important exceptions to using corticosteroids include Cryptococcal meningitis and Kaposi’s sarcoma, as they have been associated with poorer outcomes. [3] [4]
There are two common IRIS scenarios. The first is the “unmasking” of an occult opportunistic infection. The second is the “paradoxical” symptomatic relapse of a prior infection despite microbiologic treatment success. Often in paradoxical IRIS, microbiologic cultures are sterile. In either scenario, there is hypothesized reconstitution of antigen-specific T cell-mediated immunity with activation of the immune system against persisting antigen, whether present as intact organisms, dead organisms, or debris. [5]
The suppression of CD4 T cells by HIV (or by immunosuppressive drugs) causes a decrease in the body's normal response to certain infections. Not only does this make it more difficult to fight the infection, it may mean that a level of infection that would normally produce symptoms is instead undetected (subclinical infection). If the CD4 count rapidly increases (due to effective treatment of HIV, or removal of other causes of immunosuppression), a sudden increase in the inflammatory response produces nonspecific symptoms such as fever, and in some cases a worsening of damage to the infected tissue. [5]
Though these symptoms can be dangerous, they also indicate that the body may now have a better chance to defeat the infection. The best treatment for this condition is unknown. In paradoxical IRIS reactions, the events will usually spontaneously get better with time without any additional therapy. In unmasking IRIS, the most common treatment is to administer antibiotic or antiviral drugs against the infectious organism. In some severe cases, anti-inflammatory medications, such as corticosteroids are needed to suppress inflammation until the infection has been eliminated. [5]
Infections most commonly associated with IRIS include Mycobacterium tuberculosis and cryptococcal meningitis. Persons living with AIDS are more at risk for IRIS if they are starting HAART for the first time, or if they have recently been treated for an opportunistic infection (OI). It is generally advised that when patients have a low initial CD4 T cell count and OI at the time of their HIV diagnosis, they receive treatment to control the OIs before HAART is initiated approximately two weeks later. This is true for most OIs, except for OIs involving the central nervous system. [5]
Since the HIV/AIDS epidemic in the 1980s, IRIS is now mostly associated with the initiation of HIV treatment with highly active antiretroviral therapy (HAART), also referred to as antiretroviral therapy (ART). However, IRIS can still occur in the following conditions that do not involve HIV: [3] [6]
IRIS is particularly problematic in cryptococcal meningitis as IRIS is fairly common and can be fatal. [7]
IRIS has been described in immunocompetent hosts who have meningitis caused by Cryptococcus gattii and Cryptococcus neoformans var. grubii, environmental fungi which often affect immunocompetent hosts. Several weeks or even months into appropriate treatment, there is a sudden onset deterioration with worsening meningitis symptoms and progression or development of new neurological symptoms.[ citation needed ]
Magnetic resonance imaging shows increase in the size of brain lesions, and CSF abnormalities (white cell count, protein, glucose) increase. CSF culture is typically sterile, and there is no increase in CSF cryptococcal antigen titer. [8]
The increasing inflammation can cause brain injury or be fatal. [9] [10] [11]
The general mechanism behind IRIS is increased inflammation as the recovering immune system recognizes the antigens of the fungus as immunosuppression is reversed. Cryptococcal IRIS has three phases:
Three clinical predictors of cryptococcal-related paradoxical IRIS risk include:[ citation needed ]
IRIS may be the cause of paradoxically worse outcomes for cryptococcal meningitis in immunocompetent compared with immunocompromised hosts, in whom Cryptococcus neoformans is the usual pathogen. Treatment with systemic corticosteroids during IRIS may be beneficial in preventing death or progressive neurological deterioration. Steroids given to persons with anti-fungal treatment failure / cryptococcal relapse (in whom CSF cultures are not sterile) can be a fatal iatrogenic error. [13]
The clinical presentation of IRIS is variable and typically depends on the underlying OI. Common features that may be present include clinical worsening after starting ART and localized tissue inflammation. A systemic inflammatory response may or may not be present. [14] The majority of IRIS cases occur within 4 to 8 weeks of ART initiation or change. [15] However, there have been reported cases from 3 days to several months or even years after ART initiation. [16]
The following table describes the major and minor presentations in reported underlying OIs. [4]
Underlying opportunistic infection | IRIS signs/symptoms |
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Major presentations | |
Tuberculosis |
|
Mycobacterium Avium complex (MAC) infection | May be indistinguishable from active MAC infection (pulmonary disease, systemic inflammation) |
Cryptococcal meningitis | Typically worsening meningitis symptoms (rapid hearing/vision loss, ataxia, elevated intracranial pressure) |
Cytomegalovirus (CMV) retinitis | |
Hepatitis B or Hepatitis C virus |
|
Progressive multifocal leukoencephalopathy (PML) |
|
Kaposi's sarcoma (KS) |
|
Cerebral toxoplasmosis | Cerebral abscess (aka toxoplasmosis encephalitis) |
Autoimmune diseases | Flares of existing autoimmune conditions, including sarcoidosis or Grave’s disease |
Minor presentations | |
Herpes simplex virus (HSV) and Varicella zoster virus (VZV) |
|
Nonspecific dermatologic complications | Appearance or worsening of a variety of dermatologic manifestations, including folliculitis, oral and genital warts |
The diagnosis of IRIS is clinical. [17] There is no universal definition of IRIS, however there is general consensus that most of the following criteria should be met to make the diagnosis: [17]
The differential diagnosis of IRIS is broad given its varied presentation. [18] Conditions that can present similarly to IRIS are: adverse drug effects, progression of initial OI caused by medication resistance or patient non-adherence, and development of a new OI. [18]
Mild IRIS
Severe IRIS
IRIS has a reported mortality rate of 4.5%. [19] Mortality rates vary and depend on the associated OI, degree of immunosuppression, geography, and access to treatment. IRIS affecting the central nervous system has generally been associated with the highest mortality rates (13-75%). [19] [20]
IRIS was discovered in the 1980s when physicians noted paradoxical symptomatic worsening of patients being treated for pulmonary tuberculosis and leprosy. [3] There was worsened fever, weight loss, shortness of breath, and fatigue in patients with pulmonary tuberculosis and worsened skin lesions in patients with leprosy. [3] Though the mechanism was unclear at the time, these observations were attributed to a pro-inflammatory state brought on by starting treatment. [3]
Bats recovering from white-nose syndrome (WNS) may be the first known natural occurrence of IRIS, in a report released by the USGS. [21] WNS is typified by a cutaneous infection of the fungus Pseudogymnoascus destructans during hibernation, when the immune system is naturally suppressed to conserve energy through the winter. This study suggests that bats undergoing an intense inflammation at the site of infection after a return to euthermia is a form of IRIS. [22]
Viral meningitis, also known as aseptic meningitis, is a type of meningitis due to a viral infection. It results in inflammation of the meninges. Symptoms commonly include headache, fever, sensitivity to light and neck stiffness.
Cryptococcus neoformans is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to Filobasidiella neoformans. In its yeast state, it is often found in bird excrement. Cryptococcus neoformans can cause disease in apparently immunocompetent, as well as immunocompromised, hosts.
Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity and confusion or changes in behavior. It can also affect other parts of the body including skin, where it may appear as several fluid-filled nodules with dead tissue.
This is a list of AIDS-related topics, many of which were originally taken from the public domain U.S. Department of Health Glossary of HIV/AIDS-Related Terms, 4th Edition.
An opportunistic infection is an infection caused by pathogens that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune system, an altered microbiome, or breached integumentary barriers. Many of these pathogens do not necessarily cause disease in a healthy host that has a non-compromised immune system, and can, in some cases, act as commensals until the balance of the immune system is disrupted. Opportunistic infections can also be attributed to pathogens which cause mild illness in healthy individuals but lead to more serious illness when given the opportunity to take advantage of an immunocompromised host.
Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, mycobacteria, spirochetes, fungi, medications, and cancer malignancies. The testing for both meningitis and aseptic meningitis is mostly the same. A cerebrospinal fluid sample is taken by lumbar puncture and is tested for leukocyte levels to determine if there is an infection and goes on to further testing to see what the actual cause is. The symptoms are the same for both meningitis and aseptic meningitis but the severity of the symptoms and the treatment can depend on the certain cause.
AIDS-defining clinical conditions is the list of diseases published by the Centers for Disease Control and Prevention (CDC) that are associated with AIDS and used worldwide as a guideline for AIDS diagnosis. CDC exclusively uses the term AIDS-defining clinical conditions, but the other terms remain in common use.
Neuritis is inflammation of a nerve or the general inflammation of the peripheral nervous system. Inflammation, and frequently concomitant demyelination, cause impaired transmission of neural signals and leads to aberrant nerve function. Neuritis is often conflated with neuropathy, a broad term describing any disease process which affects the peripheral nervous system. However, neuropathies may be due to either inflammatory or non-inflammatory causes, and the term encompasses any form of damage, degeneration, or dysfunction, while neuritis refers specifically to the inflammatory process.
Neurosyphilis is the infection of the central nervous system in a patient with syphilis. In the era of modern antibiotics, the majority of neurosyphilis cases have been reported in HIV-infected patients. Meningitis is the most common neurological presentation in early syphilis. Tertiary syphilis symptoms are exclusively neurosyphilis, though neurosyphilis may occur at any stage of infection.
Pneumocystis pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia (PJP), is a form of pneumonia that is caused by the yeast-like fungus Pneumocystis jirovecii.
Cryptococcus gattii, formerly known as Cryptococcus neoformans var. gattii, is an encapsulated yeast found primarily in tropical and subtropical climates. Its teleomorph is Filobasidiella bacillispora, a filamentous fungus belonging to the class Tremellomycetes.
Mollaret's meningitis is a recurrent or chronic inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. Since Mollaret's meningitis is a recurrent, benign (non-cancerous), aseptic meningitis, it is also referred to as benign recurrent lymphocytic meningitis. It was named for Pierre Mollaret, the French neurologist who first described it in 1944.
Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or altered consciousness, nausea, vomiting, and an inability to tolerate light or loud noises. Young children often exhibit only nonspecific symptoms, such as irritability, drowsiness, or poor feeding. A non-blanching rash may also be present.
Fungal meningitis refers to meningitis caused by a fungal infection.
Neurovirology is an interdisciplinary field which represents a melding of clinical neuroscience, virology, immunology, and molecular biology. The main focus of the field is to study viruses capable of infecting the nervous system. In addition to this, the field studies the use of viruses to trace neuroanatomical pathways, for gene therapy, and to eliminate detrimental populations of neural cells.
The stages of HIV infection are acute infection, latency, and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, swollen lymph nodes, inflammation of the throat, rash, muscle pain, malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts, various opportunistic infections, cancers, and other conditions.
The co-epidemic of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major global health challenges in the present time. The World Health Organization (WHO) reports 9.2 million new cases of TB in 2006 of whom 7.7% were HIV-infected. Tuberculosis is the most common contagious infection in HIV-Immunocompromised patients leading to death. These diseases act in combination as HIV drives a decline in immunity while tuberculosis progresses due to defective immune status. This condition becomes more severe in case of multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Tuberculosis can occur at any stage of HIV infection. The risk and severity of tuberculosis increases soon after infection with HIV. A study on gold miners of South Africa revealed that the risk of TB was doubled during the first year after HIV seroconversion. Although tuberculosis can be a relatively early manifestation of HIV infection, it is important to note that the risk of tuberculosis progresses as the CD4 cell count decreases along with the progression of HIV infection. The risk of TB generally remains high in HIV-infected patients, remaining above the background risk of the general population even with effective immune reconstitution and high CD4 cell counts with antiretroviral therapy.
Harriet Mayanja-Kizza, MBChB, MMed, MSc, FACP, is a Ugandan physician, researcher, and academic administrator. She is the former Dean of Makerere University School of Medicine, the oldest medical school in East Africa, established in 1924.
Irini Sereti is a Greek scientist and physician. She is chief of the HIV pathogenesis section at the National Institute of Allergy and Infectious Diseases. Sereti researches immune reconstitution inflammatory syndrome, idiopathic CD4 lymphocytopenia, and immune-based therapeutic strategies of HIV investigation.
Andrew Ddungu Kambugu is a Ugandan physician who serves as The Sande-McKinnell Executive Director at Uganda Infectious Disease Institute and a Honorary Senior lecturer at Makerere University College of Sciences. He is also an Adjunct Associate Professor at the University of Minnesota. In July 2020, he was appointed to the United Nations 2021 Food System Scientific Group.
Immune Reconstitution Inflammatory Syndrome (IRIS)