Immune reconstitution inflammatory syndrome

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]

• Solid organ transplant recipients
  • After undergoing solid organ transplant (liver, kidney, pancreas, etc.), patients are prescribed immunosuppressive agents, such as tacrolimus or cyclosporine. These medications target CD4 immune cells, suppressing their function. IRIS in these patients is thought to be due to the pro-inflammatory response after withdrawal of immunosuppressants. Common infections associated with IRIS in these patients are cryptococcosis, cytomegalovirus (CMV), and tuberculosis.^[3][6]
• Neutropenic patients
  • When the absolute neutrophil count (ANC) is less than 500 per microliter, there is an increased risk of fungal and viral opportunistic infections (OI), such as Aspergillus or CMV. While the patient is immunosuppressed, these infections may remain latent and asymptomatic. However, when the ANC improves, the infections may become symptomatic and present as IRIS. Common infections associated with IRIS in these patients are invasive pulmonary aspergillosis and chronic disseminated candidiasis.^[3][6]
• Postpartum patients
  • During pregnancy, the immune system is relatively suppressed to prevent fetal rejections or
    herpes virus, tuberculosis, leprosy, viral hepatitis. Flare-ups of autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis may also occur during this period.^[3][6]
• Patients on tumor necrosis factor antagonists
  • Patients with chronic inflammatory conditions (Crohn's disease, ulcerative colitis, sarcoidosis, etc.) are often treated with TNF antagonists, such as infliximab, adalimumab, and etanercept. Tumor necrosis factors are critical in macrophage activation and subsequent granuloma formation. Therefore, TNF antagonists impair the host immune response against infections such as tuberculosis. While the patient is taking TNF antagonists, these infections may remain latent and asymptomatic. However, when these medications are discontinued, there may be an associated pro-inflammatory response causing the infection to be uncovered.^[3][6]

In cryptococcal meningitis

IRIS is particularly problematic in

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:

1. before
   HAART, with a paucity of cerebrospinal fluid
   (CSF) inflammation and defects in antigen clearance;
2. during initial
   HAART
   immune recovery, with pro-inflammatory signaling by antigen-presenting cells without an effector response; and
3. at IRIS, a
   interferon-gamma response.^[7][8][12]

Three clinical predictors of cryptococcal-related paradoxical IRIS risk include:^[citation needed]

1. lack of initial CSF pleocytosis (i.e. low CSF white blood cell count);
2. elevated C-reactive protein;
3. 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 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]

Signs and symptoms

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]

Diagnosis

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]

• Presence of AIDS with low pretreatment CD4 count, typically <100 cells/microL. An exception is in the setting of Mycobacterium tuberculosis infection, which can be reactivated with CD4 cells >200 cells/microL.^[17]
• Decrease in HIV-1 RNA levels from baseline or increase in CD4 count after starting ART^[17]
• No evidence of drug-resistant infection, bacterial superinfection, adverse drug reaction, patient non-adherence, or reduced serum drug levels (from drug-drug interactions or malabsorption).^[17]
• Clinical symptoms consistent with an inflammatory condition^[17]
• Temporal association between initiation of ART and symptom onset^[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]

Management

Mild IRIS

• For mild symptoms, treatment is focused on treating the underlying infection and symptom management. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to alleviate inflammatory symptoms, such as fever or pain. Abscess drainage, excision of painful and inflamed lymph nodes, and inhaled corticosteroids for bronchospasm from mild pulmonary inflammation may also be used when indicated.^[3][4]

Severe IRIS

• In severe IRIS, symptoms may cause permanent disability or death. Management again includes antimicrobial treatments against the underlying infection. Corticosteroids are the most commonly used intervention in these cases as they work to suppress the inflammatory response seen in IRIS, though there is limited research on their efficacy. Guidelines recommend a risk/benefit analysis prior to starting corticosteroids, especially taking into consideration the patient’s comorbidities. Common adverse effects of corticosteroids are hyperglycemia, hypertension, mental status changes, worsening of an existing infection, and increased risk of a new infection. Important exceptions include cases of Cryptococcal-IRIS with worsening meningitis symptoms (cranial nerve defects, hearing or vision changes) and cases of Kaposi's sarcoma. In these cases, corticosteroids should not be used as they have been shown to worsen outcomes.^[3][4]
• It is recommended to continue ART except in the most severe cases of IRIS. Discontinuing ART may be considered in life-threatening cases of IRIS not improved by corticosteroids, usually in central nervous system-associated IRIS. Stopping ART increases the risk of acquiring new OI and developing IRIS again when restarting ART.^[3][4]

Prognosis

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]

History

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]

In bats recovering from white-nose syndrome

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]

See also

• List of cutaneous conditions
• Jarisch-Herxheimer reaction
  , another systemic inflammatory syndrome that arises after antimicrobial treatment

References