Immune reconstitution inflammatory syndrome

Immune reconstitution inflammatory syndrome

1. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME Dr. Navin Adhikari Internal Medicine Resident

2. DEFINITION The term " immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy (ART) in HIV-infected individuals . Synonyms Immune recovery disease Immune reconstitution disease Immune reconstitution syndrome Immune restoration disease Immune rebound illness Steroid-withdrawal disease Immuno restitution disease Immune response reactions

3. RISK FACTORS L ow CD4+ T-cell count when ART is initiated D isseminated infection a short time interval between treatment of the infection and commencement of ART. Integrase strand transfer inhibitor (INSTI)-based regimens –due to faster reduction in HIV viral load.

4. PATHOGENESIS Occurs as a result of recovery of CD4+ T count which occurs biphasically . Rapid increase occurs during first 3 to 6 months of ART. Due to increase in numbers of CD45RO+ memory T cells Decreased lymphocyte apoptosis and simultaneous redistribution from peripheral lymphoid tissues into circulation. Slower increase of predominately naive CD4+ T cells (CD45RA+, CD62L+) Due to expansion of T cell clones produced by thymus prior to its age-related functional decline - secondary to thymopoiesis ART –> Rapid increase in CD8+ T lymphocytes also -> memory CD8+ cells subsequently decline and are replaced by naive CD8+ T lymphocytes -> total numbers of CD8+ T lymphocytes eventually stabilize Accompanied by : increased in vitro lymphocyte proliferation responses, and pathogen-specific delayed hypersensitivity reaction

5. TYPES Paradoxical IRIS : manifest as a worsening of previously diagnosed disease. Examples: TB, C ryptococcosis , Kaposi sarcoma and herpes zoster. Unmasking IRIS : manifest as the appearance of a previously undiagnosed disease Examples: Mycobacterium avium complex

6. EXAMPLES OF IRIS

7. Diagnosis IRIS should be considered only when the presentation cannot be explained by a new infection, expected course of a known infection or drug toxicity. IRIS is diagnosis of exclusion. Following condition should be excluded a. active OIs b. treatment failure c. side-effects of ARVs and d. ARV resistance

8. F eatures required to make the diagnosis: The presence of AIDS with a low pretreatment CD4 count (often less than 100 cells/ microL ). A positive virologic and immunological response to antiretroviral therapy . The absence of evidence of drug-resistant infection, bacterial superinfection , drug allergy or other adverse drug reactions, patient noncompliance, or reduced drug levels due to drug-drug interactions or malabsorption . The presence of clinical manifestations consistent with an inflammatory condition. A temporal association between ART initiation and the onset of clinical features of illness.

9. DIFERENTIAL DIAGNOSIS Progression of initial opportunistic infection (OI) due to antimicrobial resistance or nonadherence to prescribed drug regimens. New OI. Drug toxicity ( Eg . Abacavir hyersensitivity )

10. Similar Paradoxical inflammatory syndromes in other Conditions Treatment for tuberculosis or lepromatous leprosy Corticosteroid withdrawal. Discontinuation of antitumor necrosis factor alpha therapy. Recovery of neutropenia after cytotoxic chemotherapy. Withdrawal of immunosuppression in transplant recipients infected with Cryptococcus neoformans . Engraftment of stem cell transplantation  .

11. CLINICAL FEATURES

12. TB-IRIS M. tuberculosis is the most common pathogen involved in IRIS. Most TB-IRIS develops within the first 3 months after the initiation of ART. After initiation of ART, paradoxical iris evedent by recurrent, worsening, or new clinical or radiologic manifestations of TB develop. Common manifestations include fever, enlargement of lymph nodes, and worsening radiographic pulmonary infiltrates.

13. Tracheal compression by intrathoracic lymph nodes or massive pleural effusions can cause life-threatening dyspnea . Respiratory failure as a result of worsening pulmonary infiltrates and acute respiratory distress syndrome have occasionally been reported. N eurologic TB-IRIS accounted for 12% of cases of paradoxical TB-IRIS. Meningitis, tuberculoma , or both were the most common manifestations. TB-IRIS may cause granulomatous hepatitis, typically with tender hepatomegaly and cholestatic liver function derangement.

14. Pulmonary TB : Fever Malaise Weight loss Worsening respiratory symptoms Transient worsening of radiographic abnormalities ( new parenchymal opacities and progressive intrathoracic lymph node enlargement ) Severe respiratory compromise Adult respiratory distress syndrome . Extrapulmonary TB : Worsening lymphadenitis New pleural effusions Reappearance of fever with new infiltrates Expansion of preexisting intracranial tuberculomas Changes in ability to respond to tuberculin proteins

15. NTM-IRIS Atypical manifestations of Mycobacterium avium complex (MAC) disease in patients who were on zidovudine monotherapy suggested that IRIS may be a complication of ART. Unmasking disease is most common. Manifestsas fever, night sweats, and lymphadenitis. Peripheral lymphadenitis may suppurate and sometimes cause chronically discharging fistulas to the skin. Pulmonary and thoracic disease usually causes cough that is sometimes associated with chest pain.

16. Microscopic examination of biopsy material or aspirates from affected tissues often reveals mycobacteria , but these may not be cultured. In HIV- seropositive children vaccinated with bacille Calmette-Guérin (BCG), a BCG-associated lymphadenitis with or without abscess formation may develop after starting ART. Leprosy-associated IRIS is usually manifested as unmasking of previous subclinical Mycobacterium leprae infection, with a borderline and type I reactional state.

17. CRYPTOCOCCOSIS IRIS Presents as recurrence of previously treated cryptococcal meningitis. Unmasking inflammatory reactions are also reported. The time of onset of C-IRIS varies from 4 days to around 3 years after initiation of ART. In addition to recurrent meningitis, the central nervous system (CNS) features of C-IRIS include intracranial cryptococcoma or abscesses, spinal cord abscesses, recalcitrant raised intracranial pressure, optic disc swelling, cranial nerve lesions, dysarthria , hemiparesis , and paraparesis . Extracranial manifestations of C-IRIS include lymphadenitis, eye disease, suppurating soft tissue lesions, and pulmonary disease that may include cavitating or nodular lesions

18. In cryptococcal meningitis, cerebrospinal fluid with white blood cell counts of 25 cells/µL or less and protein levels of 50 mg/ dL or less are associated with the development of C-IRIS. CSF profiles at paradoxical C-IRIS may show an increased white blood cell count and an increased opening pressure of greater than 25 cm H2O, but these features overlap significantly with those observed in patients with non–IRIS-related relapses of cryptococcal meningitis.

19. Pneumocystosis -IRIS It is usually characterized by fever, cough, dyspnea , chest discomfort, and patchy alveolar infiltrates on the chest radiograph In some patients, organizing pneumonia develops. This condition is relatively rare, occurring in less than 5% of patients treated for PJP prior to ART.

20. Cytomegalovirus IRIS Eye disease is the most common manifestation of IRIS associated with cytomegalovirus infection. Retinitis usually develops during the first few weeks of ART as a paradoxical worsening of treated retinitis or as a new manifestation of CMV retinitis. Previously treated CMV infection is the most common cause of immune recovery uveitis (IRU), which results from the restoration of an immune response against residual CMV antigens in the eye. It may develop up to 21 months after ART is commenced C linical manifestations vary in severity from a transient vitreitis to persistent uveitis , papillitis , cystoid macular edema , and detachment of epiretinal membranes.

21. PML-IRIS Progressive multifocal leukoencephalopathy (PML) occurs when cellular immune responses fail to control JCV infection of oligodendrocytes and astrocytes . ART is effective in some patients, presumably because it enhances cellular immune responses against JCV antigens. ART may also result in a paradoxical worsening of established PML or in unmasking of subclinical JCV infection and appearance of PML for the first time. The median time at onset is 7 weeks on ART, and most cases occur within the first 3 months but very occasionally as late as 26 months.

22. Management IRIS is generally self-limiting, and interruption of ART is rarely indicated. Patient may need to be reassured in the face of protracted symptoms to prevent discontinuation of or poor adherence to ART. Anti-inflammatory therapy should not be given routinely but be reserved for patients with severe inflammation, particularly when it is life-threatening, or with significant symptoms. Corticosteroid therapy is used most often, but its effectiveness may vary from one type of IRIS to another.

23. A randomized controlled trial in South Africa demonstrated that corticosteroids (prednisone 1.5 mg/kg/day for 2 weeks, then 0.75 mg/kg/day for 2 weeks) are a safe and effective treatment option for paradoxical TB-IRIS. C orticosteroid therapy in HIV patients who are already very immunodeficient should be started only after weighing all considerations Corticosteroid therapy for IRIS affecting the eye should be supervised by an ophthalmologist.

24. PREVENTION E arlier HIV diagnosis and initiation of ART before a decline of the CD4 count to below 200 cells/ mm3 I mproved screening for OIs before initiating ART, especially TB, cryptococcal disease and CMV O ptimal management of OIs before initiating ART. D elaying the introduction of ART so that the OI can be fully treated. in cryptococcal meningitis, ART should be deferred for 5 weeks , as earlier initiation increases the risk of death; and in tuberculosis, ART should be deferred until 8 weeks (except if the CD4 count is < 50 cells/mm) to prevent IRIS.

25. However , randomized controlled trials demonstrated that for patients with HIV-associated TB and CD4+ T-cell count less than 50 cells/µL, the survival benefit of starting ART within the first 2 weeks of TB therapy outweighs the risk for IRIS and other adverse events. A randomized controlled trial demonstrated that the risk of paradoxical TB-IRIS could be reduced by 30% in high-risk patients (CD4+ T-cell count ≤100 cells/µL) with HIV-associated TB starting ART by prescribing prednisone for the first 4 weeks of ART (40 mg daily for 2 weeks then 20 mg daily for 2 weeks).

26. PROGNOSIS highly variable because of differences in the extent of the infection Most cases of IRIS are self-limited, and outcomes are usually good Mortality and hospitalization rates are particularly high when TB-IRIS or C-IRIS affects the CNS Mortality rates of 53% have been reported for paradoxical PMLIRIS and 31% for unmasking PML-IRIS. Furthermore, patients who survive PML-IRIS may have neurologic sequelae such as hemiparesis or seizure. L ymphadenitis resulting from TB-IRIS11 or NTM-IRIS may exerience recurrent relapses

27. REFERENCES Goldman-Cecil_Medicine_2-Volume_Set_26th_Edition_by_Lee_Gold Uptodate 2021 Mandell , Douglas, and Bennett's Principles and Practice of Infectious  Disease