Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of

AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...

, in which the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

begins to recover, but then responds to a previously acquired

opportunistic infection An opportunistic infection is an infection caused by pathogens (bacteria, fungi, parasites or viruses) that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune ...

with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.

In HIV infection and immunosuppression

The suppression of CD4

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

s 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 Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

such as fever, and in some cases a worsening of damage to the infected tissue. There are two common IRIS scenarios. The first is the “unmasking” of an

occult The occult, in the broadest sense, is a category of esoteric supernatural beliefs and practices which generally fall outside the scope of religion and science, encompassing phenomena involving otherworldly agency, such as magic and mysticism a ...

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 following HIV therapy against persisting antigen, whether present as intact organisms, dead organisms, or debris. 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 An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

antiviral Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do no ...

drugs against the infectious organism. In some severe cases, anti-inflammatory medications, such as

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

s are needed to suppress inflammation until the infection has been eliminated. Infections most commonly associated with IRIS include ''

Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...

'' and

cryptococcal meningitis Cryptococcosis is a potentially fatal mycosis, fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, shortness of breath, difficulty breathing, chest pain and fever are seen when the ...

. Persons living with AIDS are more at risk for IRIS if they are starting for the first time, or if they have recently been treated for an

(OI). It is generally advised that when patients have low initial CD4 T cell count and opportunistic infection at the time of their HIV diagnosis, they receive treatment to control the opportunistic infections before HAART is initiated approximately two weeks later. This is true for most OIs, except for OIs involving the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

In cryptococcal meningitis

IRIS is particularly problematic in

as IRIS is fairly common and can be fatal. IRIS has been described in immunocompetent hosts who have meningitis caused by ''

Cryptococcus gattii ''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 belongi ...

'' 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.

Magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

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. The increasing inflammation can cause brain injury or be fatal. 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: # before

HAART The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple ...

, with a paucity of

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

(CSF) inflammation and defects in antigen clearance; # during initial

immune recovery, with pro-inflammatory signaling by antigen-presenting cells without an effector response; and # at IRIS, a

cytokine storm A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Norma ...

with a predominant type-1 helper T-cell

interferon-gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

response. Three clinical predictors of cryptococcal-related paradoxical IRIS risk include: # lack of initial CSF

pleocytosis In medicine, pleocytosis (or pleiocytosis) is an increased cell count (from Greek ''pleion'', "more"), particularly an increase in white blood cell count, in a bodily fluid, such as cerebrospinal fluid. It is often defined specifically as an increa ...

(i.e. low CSF white blood cell count); # elevated

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 ...

; # failure to sterilize the CSF before immune recovery. IRIS may be the cause of paradoxically worse outcomes for cryptococcal meningitis in immunocompetent compared with immunocompromised hosts, in whom ''

Cryptococcus neoformans ''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' ...

'' 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 Iatrogenesis is the causation of a disease, a harmful complication, or other ill effect by any medical activity, including diagnosis, intervention, error, or negligence. "Iatrogenic", ''Merriam-Webster.com'', Merriam-Webster, Inc., accessed 2 ...

error.

In bats recovering from white-nose syndrome

Bats recovering from

white-nose syndrome White-nose syndrome (WNS) is a fungal disease in North American bats which has resulted in the dramatic decrease of the bat population in the United States and Canada, reportedly killing millions as of 2018. The condition is named for a distincti ...

(WNS) may be the first known natural occurrence of IRIS, in a report released by the USGS. WNS is typified by a cutaneous infection of the fungus ''

Pseudogymnoascus destructans ''Pseudogymnoascus destructans'' (formerly known as ''Geomyces destructans'') is a psychrophilic (cold-loving) fungus that causes white-nose syndrome (WNS), a fatal disease that has devastated bat populations in parts of the United States and Can ...

'' 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.

In HIV infection and immunosuppression

In cryptococcal meningitis

In bats recovering from white-nose syndrome

See also

References

Further reading