Continuing Education Activity

Immune reconstitution inflammatory syndrome (IRIS) is a state of hyperinflammatory response that usually occurs in the first six months of treatment of HIV/AIDS patients. It is a potential complication of the use of highly active antiretroviral therapy (HAART). The overall incidence of IRIS is still unknown. However, some studies report that up to 25 to 30% of HIV patients who are on antiretroviral therapy have IRIS. This activity outlines the risk factors, pathophysiology, clinical presentation, and the interprofessional team's role in managing immune reconstitution syndrome.

Objectives:

• Assess the prevalence of immune reconstitution inflammatory syndrome in HIV/AIDS patients that are initiated on HAART.
• Identify the risk factors associated with an increased risk of immune reconstitution inflammatory syndrome while being treated with HAART.
• Evaluate the common clinical presentation associated with immune reconstitution inflammatory syndrome.
• Communicate some interprofessional team strategies that can be used to improve patient outcomes for individuals who present with immune reconstitution inflammatory syndrome.

Introduction

Human immunodeficiency virus (HIV) targets the immune system by depleting CD4+ T lymphocytes and predisposing patients to an increased risk of opportunistic infections. Highly active antiretroviral therapy (HAART) leads to restoring CD4+ T lymphocytes and normalizing an immune response against pathogens.[1][2] This improvement in immunity has resulted in significant improvement in the quality of life and health care outcomes in HIV patients.[3] Although the introduction of HAART has been a landmark in preventing HIV-related deaths, there are still issues with HAART therapy. Since its inception, there have been several reported side effects of HAART and its possible interactions with other medications. Side effects can range from mild-severe allergic reactions, idiosyncratic reactions, and hematological disorders to altered drug metabolism.[4][5] Additionally, using HAART therapy, the serum levels of certain medications can increase due to drug interaction, causing significant side effects.[6]

Another potential complication that may arise with HAART therapy is immune reconstitution inflammatory syndrome (IRIS). IRIS is a poorly understood disease whose exact mechanism is not yet fully known. It is a state of dysregulated, hyper-inflammatory response against opportunistic infections that usually occurs in the first 6 months of treatment of HIV/AIDS patients.[7][8][9] IRIS is a potential complication of highly active antiretroviral therapy (HAART) and was first reported in the 1990s. It can lead to poor adherence and compliance with HAART in HIV/AIDS patients.[10][11][12] It can also increase the risk of drug resistance with HAART, worsen HIV progression to AIDS, and decrease the quality of life in the infected population. Overall, the IRIS has been associated with significant morbidity and mortality in HIV/ AIDS patients. This topic provides a comprehensive review of the risk factors, pathophysiology, associated microorganisms, clinical presentations, and treatment of IRIS in HIV patients following the initiation of HAART.

Etiology

The Historical Aspects of the IRIS

Immune reconstitution inflammatory syndrome (IRIS) was first discovered in the 1980s in patients with tuberculosis and Leprosy who were receiving treatment. Physicians at that time noted a paradoxical worsening of fever, weight loss, fatigue, and shortness of breath in patients with pulmonary TB and worsening of skin lesions in patients with Leprosy after initiation of treatment.[13][14][15] The mechanism for this was not clear at that time. Still, it was later attributed to a shift from a relative anti-inflammatory state in untreated TB and Leprosy to a pro-inflammatory state that occurs once the immune system recovers after initiation of treatment. Following the HIV/AIDS epidemic in the 1980s, and with HAART therapy initiation, IRIS is now a phenomenon that is most commonly associated with HIV treatment. It can, however, occur in conditions or scenarios that are not HIV-related.

The following are non-HIV-related conditions where IRIS has been observed:

1. Solid Organ Transplant Recipients

Solid organ transplant recipients (eg, liver and kidney transplants) are placed on immunosuppressive agents such as tacrolimus or cyclosporine. These agents target CD4-positive cells and suppress their functioning. IRIS seen in solid organ transplant recipients is thought to be secondary to the antiinflammatory response seen after withdrawal of these immunosuppressive agents. Cryptococcosis, Cytomegalovirus disease, and tuberculosis are the most common infections associated with IRIS in solid organ transplant recipients.[16] 

2. Postpartum Period 

Pregnancy is a period of a relatively immunocompromised state. During pregnancy, there is a shift to the activation of Th2 cells and an increased IL-4, IL-5, and IL-10. There is also a suppression of Th1 cells and associated cytokines (IL-12, TNF-a). This results in a state of anti-inflammatory response, which is needed during pregnancy to prevent any fetal rejections or miscarriages. However, after pregnancy, this process reverses, which results in a relatively pro-inflammatory state immediately postpartum. Thus, the immediate postpartum period (3 to 6 weeks) has an increased risk of IRIS, most commonly with cryptococcosis, herpes virus infection, human papillomavirus reactivation, leprosy, tuberculosis, viral hepatitis, and a flare-up of autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis.

3. Neutropenic Patients

Patients with an absolute neutrophil count (ANC) below 500 per microliter are at increased risk of fungal and viral opportunistic infections (Aspergillus infections, CMV). These infections might initially be latent or have subacute presentations but become clinically apparent only after the neutrophil counts improve, thus presenting as IRIS. The most commonly observed IRIS in neutropenic patients has been associated with invasive pulmonary aspergillosis and chronic disseminated candidiasis.

4. Patients on Tumor Necrosis Factor Antagonists (TNF antagonists)

TNF antagonists such as infliximab, adalimumab, certolizumab, and etanercept treat chronic inflammatory conditions such as ulcerative colitis, Crohn disease, or sarcoidosis. Tumor necrosis factors play an integral role in macrophage activation and granuloma formation. Thus, TNF antagonists can significantly impair the host response against infections such as TB. These TB infections can be latent while using TNF antagonists, but once these medications are discontinued, there is a subsequent macrophage activation, leading to IRIS associated with TB.

Epidemiology

Since the introduction of the first HAART drug, zidovudine, in 1987 and the initiation of combination therapy in 1996, there has been a significant decrease in the incidence of HIV-related opportunistic infections. Several studies have demonstrated clear mortality benefits of HAART therapy in HIV/ AIDS. Its inception has led to a dramatic improvement in HIV-related outcomes, including mortality outcomes in HIV patients.

The use of HAART in HIV/AIDS provides the following benefits:

1. It decreases HIV viral load. 
2. It leads to an increase in CD4+ T lymphocytes.
3. It restores protective humoral and cellular immune functions against infections. 

The potential adverse outcomes from the use of HAART are outlined below:

A. Side effects of HAART drugs: The most frequently encountered adverse effects of HAART include nausea, lethargy, cold, loss of taste sensation, anxiety, anorexia, depression, and peripheral neuropathy. Other potential side effects include anemia, lactic acidosis, pancreatitis, hepatotoxicity, and lipodystrophy, specifically noted with nucleoside reverse transcriptase inhibitors (NRTI), Non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PIs) use. Prior studies have reported that HAART-related side effects have resulted in medication non-compliance, which has led to drug resistance, progression to AIDS, and increased mortality.[17] 

B. Immune reconstitution syndrome (IRIS): IRIS is a potential complication of initiation of HAART. It can occur in up to a third of cases of HIV patients initiated on HAART. It is a state of hyper-inflammatory response against latent infections that happens after the improvement in CD4 cell count and immune response once therapy for HIV has started. Commonly reported opportunistic pathogens are cytomegalovirus, mycobacterium, cryptococcus, Epstein-Barr virus, pneumocystis, JC virus, hepatitis B, and C. Therefore, the knowledge of any latent infections in patients is crucial before starting HAART in HIV/AIDS patients. The clinical presentation and severity of IRIS depend on the organism involved, the infection's location, and the inflammatory response's severity.[7][8][9]

C. The risk for drug-drug interactions:  Drug-drug interactions can occur between HAART and drugs used for treating other conditions in patients with HIV/AIDS. The most commonly encountered drug interactions in HIV/AIDS patients treated with HAART drugs occur in patients receiving treatment for cancer and patients receiving treatment for other co-infections like tuberculosis and fungal infections. Drugs metabolized by the cytochrome P450 enzyme system include NNRTI, PIs, anti-tubercular, and anti-cancer drugs. These drugs interact with each other either by inducing or inhibiting the efficacy of one another.[18] The common mechanism of drug-drug interactions and examples are as follows:[19] 

Increase in Serum Level of Drugs and Increased Risk of Drug-related Side Effects

• The use of fluconazole and zidovudine (ZDV) can increase the serum concentration of ZDV and lead to an increased risk of hepatotoxicity and hemato-toxicity.
• NSAID use with efavirenz (EFV) can increase serum concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) and cause an increase in the risk of nephrotoxicity.
• Co-administration of morphine and EFV increases the serum concentration of morphine, resulting in respiratory depression.

Decreased Serum Level of Drugs and Decreased Therapeutic Efficacy

• Use of anti-epileptics such as carbamazepine can decrease the levels of NNRTI (non-nucleoside reverse transcriptase inhibitor)
• Rifampicin for treatment of TB can decrease serum concentrations of efavirenz (EFV) and zidovudine (ZDV)

QTc Prolongation and Increased Risk of Arrhythmia

• The use of haloperidol with protease inhibitors (PI) or azithromycin with ZDV can lead to an increase in QTc and result in cardiac arrhythmias.

Increased Risk of Organ Toxicity

• Simultaneous use of nitrofurantoin and ZDV can increase myelosuppression associated with both agents.
• The combination of isoniazid and stavudine can increase the risk of neuropathy associated with isoniazid.

The prevalence of IRIS is likely to increase with the increasing use of HAART in HIV patients. Some studies reported that up to 25% to 30% of HIV patients on antiretroviral therapy have IRIS.[20][21] The prevalence of IRIS in non-HIV patients such as neutropenic patients, women in the post-partum period, patients on TNF-alpha blockers, or solid organ transplant recipients on immunosuppressive therapy is not known. 

Risk factors for IRIS

The risk factors for IRIS in non-HIV patients are not fully understood. However, similar to HIV patients, an abrupt shift from an anti-inflammatory state to a pro-inflammatory state would cause an increased risk for IRIS. For example, patients on TNF-alpha blocking agents or high doses of steroids who are abruptly taken off of medications or neutropenic patients who have an abrupt improvement in white cell counts following allogeneic bone marrow or stem cell transplantations.[16][22]

In the case of HIV patients receiving HAART based on prior observational studies, the following are the risk factors for IRIS:[23]

1. Starting HAART treatment at a younger age or in male patients has shown an association with an increased risk of developing IRIS.

      2. CD4+T cell count is less than 100 cells per microliter when initiating HAART.[24]

      3. An accelerated rise in CD4 count following treatment with HAART.

      4. Rapid HIV RNA viral suppression within ninety days of HAART increases the risk of immune reconstitution syndrome.

      5. Pre-existing latent opportunistic infection with a high antigenic burden increases the risk and severity of IRIS. 

      6. Initiating HAART within a short time interval (30 days) after completing treatment for opportunistic infection.

      7. Studies have also suggested that genetics play a role in determining who is at an increased risk for IRIS, particularly in herpes and mycobacterial infections (HLA-A, -B44, -DR4 associated with herpes virus IRIS) and TNFA-308*1, IL6-174*G (associated with mycobacterial IRIS).[21][25]

Pathophysiology

Pathogenesis of IRIS in HIV patients: [26] [27] [28] [29]

Immune reconstitution inflammatory syndrome has been extensively studied in HIV patients receiving HAART. The terms "unmasking," "unregulated," and "paradoxical" are often used to describe the state of hyper-inflammatory response seen with the IRIS. Patients who are HIV positive and have low CD4 positive cell count usually start seeing a decrease in viral load within the first 1 to 2 weeks after initiation of HAART. An improvement in CD4 counts usually occurs in the first 3 to 6 months of initiation of HAART. As mentioned above, having a low CD4 count and disseminated latent infection before initiating HAART, rapid improvements in CD4 count, and suppression of infection after HAART initiation are all risk factors for IRIS. The underlying mechanism of IRIS is complex and is thought to be due to an imbalance between anti-inflammatory cytokines and pro-inflammatory cytokines that occurs rapidly after the recovery of immune function in HIV patients initiated on HAART. After initiation of HAART, there is an increase in CD4 count. This includes rapidly increasing memory CD4 positive T cell counts due to decreased apoptosis and lymphocyte redistribution from peripheral lymphoid tissues. A slower increase follows this in counts of naive CD4-positive T cells. Later, during the treatment, there is a clonal proliferation of these CD4-positive cells, causing a further increase in cell counts. Along with CD4 positive T cells, there is also improvement in CD8 positive T cells. 

This dramatic improvement in CD4 positive and CD8 positive T cell counts improves cell-mediated and antibody-mediated immunity. It can lead to the following:

1. An excess pathogen-specific cellular immune response.
2. Decrease in the capacity of regulatory T cells to regulate and suppress inflammation.
3. Uncoupling of both innate and acquired immunity.

This culminates in a hyperinflammatory response against underlying pathogens, culminating in IRIS symptoms.

History and Physical

Opportunistic pathogens such as Mycobacterium, fungi, viruses, and parasites can cause latent or subacute infections in HIV/AIDS patients. Due to an immunodeficient state and lack of inflammatory response, the patient can remain asymptomatic. However, after HAART initiation, an improvement in an immune-mediated inflammatory response is anticipated. This hyper-inflammatory response is the hallmark of IRIS. The clinical presentation depends on the underlying pathogen and organ/system involved and the severity of the inflammatory response.[30]

There is no universal definition of IRIS or broad consensus on diagnostic criteria. Still, the following criteria usually need to be met before the diagnosis of IRIS in HIV-positive patients:

1. The patient should be HIV-positive.
2. The patient should receive HAART with either a decrease in HIV-1 RNA level from baseline or an increase in CD4+ cells from baseline or both. 
3. Clinical symptoms should be consistent with an inflammatory process.
4. Clinical course not consistent with:

   • Expected course of previously diagnosed OI.
   • Expected course of newly diagnosed OI.
   • Drug toxicity or side effects.[31][32] 

The most common organism-specific clinical manifestations of IRIS are as follows:

Table

Organism Clinical features

Evaluation

The following table summarizes the investigative approaches for IRIS based on the suspected micro-organism.

Table

Micro-organism suspected as the source of IRIS:                                           (more...)

Approaches to prevent IRIS in HIV patients: [37]

1. The presence of latent or subacute infections with high antigen burden has been associated with the onset and severity of the IRIS. Thus, screening for latent infections, eg, TB screening with PPD test/Interferon-gamma test, cryptococcal antigen screening for latent cryptococcal infections, should be done in every patient before starting the HAART. 
2. Patients who are at high risk of having severe IRIS, eg, HIV patients with a known Pneumocystis jirovecii infection, can be started on steroids empirically before or during the initiation of HAART to minimize the risk and severity of IRIS.

Treatment / Management

The management of immune reconstitution inflammatory syndrome should focus on symptom control. It is equally important that the treatment includes initiating anti-microbial agents for the underlying opportunistic infection associated with the IRIS. It is also highly recommended to continue HAART unless there is evidence of severe HAART-related toxicity or IRIS with central nervous system (CNS) involvement.[20] The current guidelines recommend initiating HAART within 2 weeks of diagnosing most opportunistic infections. However, special consideration must be given to opportunistic infections involving the CNS (eg, cryptococcal and tubercular meningitis). HAART may be delayed further due to the risk of potentially fatal CNS immune reconstitution inflammatory syndrome.

Supportive management includes hydration, correcting electrolyte abnormalities, and optimizing nutritional status. Mild symptoms of IRIS, such as fever and pain, can be managed with paracetamol or with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with severe lung disease causing acute hypoxic respiratory failure (eg, pneumonitis secondary to Pneumocystis jirovecii) and CNS disease such as Cryptococcus-related CNS IRIS are likely to benefit from steroid use. For patients with severe CNS-IRIS resistance to steroids, biological agents such as TNF-alpha antagonists can be used. Patients with CMV-IRIS can benefit from Intraocular steroid administration.[37][38][39][40]

Differential Diagnosis

Immune reconstitution inflammatory syndrome has a heterogeneous presentation and can sometimes be difficult to diagnose. The following conditions can closely mimic the IRIS and must be considered or ruled out before the diagnosis of the IRIS is made.[31][32]

1. Side effects of HAART therapy or anti-microbial treatment. 2. Resistance to anti-microbial agents and progression of opportunistic infections (OI) as a result. 3. Lack of adherence to anti-microbial agents leads to worsening existing OI. 4. New untreated opportunistic infections.

Prognosis

The majority of cases of immune reconstitution inflammatory syndrome are mild and self-limiting. However, severe IRIS with CNS or pulmonary involvement can potentially lead to death or permanent impairment.[30][41]

Complications

Timely identification and management of IRIS are important as severe IRIS can be associated with complications, as outlined below: 

1. TB-IRS and Cryptococcus-IRS can lead to death due to acute hypoxic respiratory failure and CNS complications.[33][34][33]
2. Progressive multifocal leukoencephalopathy (PML) can be a potentially fatal demyelinating CNS disease due to the JC virus-associated IRS.[42]
3. Malignancies such as Kaposi sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma have been associated with the IRIS.[43]
4. Permanent blindness in case of severe CMV keratitis.[44]

Enhancing Healthcare Team Outcomes

Immune reconstitution inflammatory syndrome (IRIS) is a state of a dysregulated and excess immune response against latent or subacute opportunistic infections that can occur in up to one-third of HIV patients following HAART initiation. IRIS can also be seen in non-HIV patients with latent infections, such as in females in the post-partum period, patients on TNF-alpha blockers, neutropenic patients with stem cell transplants, and patients with a history of solid organ transplants on immunosuppressants. Its clinical presentation can be heterogeneous and depends on the underlying organism causing the latent infection, the location of the infection, and the severity of the inflammatory response following immune recovery.

The diagnosis of IRIS can be challenging as its clinical presentation can be similar to drug-related side effects or progression of existing opportunistic infections due to lack of adherence or resistance of anti-microbial agents. Timely identification of IRIS can lead to avoidance of complications, which, in the case of severe CNS-IRIS or pulmonary IRIS, can be life-threatening. Thus, HIV-positive patients initiated on HAART need close follow-up with an interprofessional team consisting of health care professionals, including primary care doctors, infectious disease specialists, pharmacists, and nurses, to monitor for symptoms of IRIS and timely initiation of treatment.

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References

1.

Vidya Vijayan KK, Karthigeyan KP, Tripathi SP, Hanna LE. Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 Infections. Front Immunol. 2017;8:580. [PMC free article: PMC5440548] [PubMed: 28588579]

2.

Sadiq U, Shrestha U, Guzman N. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 22, 2023. Prevention of Opportunistic Infections in HIV/AIDS. [PubMed: 30020717]

3.

Martin GE, Frater J. Post-treatment and spontaneous HIV control. Curr Opin HIV AIDS. 2018 Sep;13(5):402-407. [PubMed: 29878914]

4.

Common side effects of HIV medicines. Am Fam Physician. 2011 Jun 15;83(12):1456-8. [PubMed: 21671546]

5.

Nwaobasi E, Oleske JM. Toxicities of antiretroviral therapy in children. AIDS Read. 2006 Oct;16(10):537-40, 544-6,549-50, 552-4. [PubMed: 17096472]

6.

Santos WM, Secoli SR, Padoin SM. Potential drug interactions in patients given antiretroviral therapy. Rev Lat Am Enfermagem. 2016 Nov 21;24:e2832. [PMC free article: PMC5173305] [PubMed: 27878224]

7.

Lai RP, Meintjes G, Wilkinson RJ. HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Semin Immunopathol. 2016 Mar;38(2):185-98. [PMC free article: PMC4779131] [PubMed: 26423994]

8.

Sueki H, Mizukawa Y, Aoyama Y. Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients. J Dermatol. 2018 Jan;45(1):3-9. [PubMed: 28944502]

9.

Manzardo C, Guardo AC, Letang E, Plana M, Gatell JM, Miro JM. Opportunistic infections and immune reconstitution inflammatory syndrome in HIV-1-infected adults in the combined antiretroviral therapy era: a comprehensive review. Expert Rev Anti Infect Ther. 2015 Jun;13(6):751-67. [PubMed: 25860288]

10.

Bowen L, Nath A, Smith B. CNS immune reconstitution inflammatory syndrome. Handb Clin Neurol. 2018;152:167-176. [PMC free article: PMC11384471] [PubMed: 29604974]

11.

Gopal R, Rapaka RR, Kolls JK. Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. Eur Respir Rev. 2017 Jan;26(143) [PMC free article: PMC5642276] [PubMed: 28049128]

12.

Pérez-Rueda M, Hernández-Cabrera M, Francés-Urmeneta A, Angel-Moreno A, Pisos-Álamo E, Jaén-Sánchez N, Carranza-Rodríguez C, Pérez-Arellano JL. Immune Reconstitution Inflammatory Syndrome in HIV-Infected Immigrants. Am J Trop Med Hyg. 2017 Oct;97(4):1072-1077. [PMC free article: PMC5637585] [PubMed: 28820685]

13.

Sansonetti P, Lagrange PH. The immunology of leprosy: speculations on the leprosy spectrum. Rev Infect Dis. 1981 May-Jun;3(3):422-69. [PubMed: 7025147]

14.

Chambers ST, Hendrickse WA, Record C, Rudge P, Smith H. Paradoxical expansion of intracranial tuberculomas during chemotherapy. Lancet. 1984 Jul 28;2(8396):181-4. [PubMed: 6146749]

15.

Campbell IA, Dyson AJ. Lymph node tuberculosis: a comparison of various methods of treatment. Tubercle. 1977 Dec;58(4):171-9. [PubMed: 601870]

16.

Sun HY, Singh N. Immune reconstitution inflammatory syndrome in non-HIV immunocompromised patients. Curr Opin Infect Dis. 2009 Aug;22(4):394-402. [PubMed: 19483618]

17.

Al-Dakkak I, Patel S, McCann E, Gadkari A, Prajapati G, Maiese EM. The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: a systematic review and meta-analysis. AIDS Care. 2013;25(4):400-14. [PMC free article: PMC3613968] [PubMed: 22908886]

18.

Berretta M, Caraglia M, Martellotta F, Zappavigna S, Lombardi A, Fierro C, Atripaldi L, Muto T, Valente D, De Paoli P, Tirelli U, Di Francia R. Drug-Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection. Front Pharmacol. 2016;7:71. [PMC free article: PMC4811911] [PubMed: 27065862]

19.

Schlaeppi C, Vanobberghen F, Sikalengo G, Glass TR, Ndege RC, Foe G, Kuemmerle A, Paris DH, Battegay M, Marzolini C, Weisser M., Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) study group. Prevalence and management of drug-drug interactions with antiretroviral treatment in 2069 people living with HIV in rural Tanzania: a prospective cohort study. HIV Med. 2020 Jan;21(1):53-63. [PMC free article: PMC6916175] [PubMed: 31532898]

20.

Bosamiya SS. The immune reconstitution inflammatory syndrome. Indian J Dermatol. 2011 Sep-Oct;56(5):476-9. [PMC free article: PMC3221202] [PubMed: 22121257]

21.

Sharma SK, Soneja M. HIV & immune reconstitution inflammatory syndrome (IRIS). Indian J Med Res. 2011 Dec;134(6):866-77. [PMC free article: PMC3284095] [PubMed: 22310819]

22.

Mehta RS, Rezvani K. Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection. Virulence. 2016 Nov 16;7(8):901-916. [PMC free article: PMC5160395] [PubMed: 27385018]

23.

Murdoch DM, Venter WD, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther. 2007 May 08;4:9. [PMC free article: PMC1871602] [PubMed: 17488505]

24.

Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS. 2008 Mar 12;22(5):601-10. [PubMed: 18317001]

25.

Price P, Morahan G, Huang D, Stone E, Cheong KY, Castley A, Rodgers M, McIntyre MQ, Abraham LJ, French MA. Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS. 2002 Oct 18;16(15):2043-7. [PubMed: 12370503]

26.

Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, Leonard JM, Danner SA, Miedema F, Schellekens PT. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med. 1998 Feb;4(2):208-14. [PubMed: 9461195]

27.

Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debré P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997 Jul 04;277(5322):112-6. [PubMed: 9204894]

28.

Antonelli LR, Mahnke Y, Hodge JN, Porter BO, Barber DL, DerSimonian R, Greenwald JH, Roby G, Mican J, Sher A, Roederer M, Sereti I. Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome. Blood. 2010 Nov 11;116(19):3818-27. [PMC free article: PMC2981537] [PubMed: 20660788]

29.

Franco JM, Rubio A, Martínez-Moya M, Leal M, Merchante E, Sánchez-Quijano A, Lissen E. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood. 2002 May 15;99(10):3702-6. [PubMed: 11986226]

30.

Walker NF, Scriven J, Meintjes G, Wilkinson RJ. Immune reconstitution inflammatory syndrome in HIV-infected patients. HIV AIDS (Auckl). 2015;7:49-64. [PMC free article: PMC4334287] [PubMed: 25709503]

31.

Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, Gathe JC, Visnegarwala F, Trautner BW. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore). 2002 May;81(3):213-27. [PubMed: 11997718]

32.

Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother. 2006 Feb;57(2):167-70. [PubMed: 16354748]

33.

Machuca I, Vidal E, de la Torre-Cisneros J, Rivero-Román A. Tuberculosis in immunosuppressed patients. Enferm Infecc Microbiol Clin (Engl Ed). 2018 Jun-Jul;36(6):366-374. [PubMed: 29223319]

34.

Longley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflammatory syndrome. Curr Opin Infect Dis. 2013 Feb;26(1):26-34. [PubMed: 23242412]

35.

Ishii K, Yamamoto F, Homma S, Okada Y, Nakamichi K, Saijo M, Tamaoka A. Probable progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with immunosuppressant dose reduction following lung transplantation: a case report and literature review. BMC Neurol. 2019 Oct 31;19(1):263. [PMC free article: PMC6822459] [PubMed: 31672142]

36.

Gupta AO, Singh N. Immune reconstitution syndrome and fungal infections. Curr Opin Infect Dis. 2011 Dec;24(6):527-33. [PubMed: 22025021]

37.

Shahani L, Hamill RJ. Therapeutics targeting inflammation in the immune reconstitution inflammatory syndrome. Transl Res. 2016 Jan;167(1):88-103. [PubMed: 26303886]

38.

Marais S, Wilkinson RJ, Pepper DJ, Meintjes G. Management of patients with the immune reconstitution inflammatory syndrome. Curr HIV/AIDS Rep. 2009 Aug;6(3):162-71. [PubMed: 19589302]

39.

Sitapati AM, Kao CL, Cachay ER, Masoumi H, Wallis RS, Mathews WC. Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab. Clin Infect Dis. 2010 Jan 15;50(2):e7-10. [PubMed: 20001539]

40.

Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, Oni T, Maartens G. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010 Sep 24;24(15):2381-90. [PMC free article: PMC2940061] [PubMed: 20808204]

41.

Murthy AR, Marulappa R, Hegde U, Kappadi D, Ambikathanaya UK, Nair P. Treatment guidelines and prognosis of immune reconstitution inflammatory syndrome patients: a review. J Int Oral Health. 2015 Apr;7(4):92-5. [PMC free article: PMC4409807] [PubMed: 25954081]

42.

Bauer J, Gold R, Adams O, Lassmann H. Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS). Acta Neuropathol. 2015 Dec;130(6):751-64. [PubMed: 26323992]

43.

Gopal S, Patel MR, Achenbach CJ, Yanik EL, Cole SR, Napravnik S, Burkholder GA, Mathews WC, Rodriguez B, Deeks SG, Mayer KH, Moore RD, Kitahata MM, Richards KL, Eron JJ. Lymphoma immune reconstitution inflammatory syndrome in the center for AIDS research network of integrated clinical systems cohort. Clin Infect Dis. 2014 Jul 15;59(2):279-86. [PMC free article: PMC4102912] [PubMed: 24755860]

44.

Ma N, Ye JJ. [Ocular immune reconstitution inflammatory syndrome]. Zhonghua Yan Ke Za Zhi. 2016 Feb;52(2):150-3. [PubMed: 26906710]

Disclosure: Sushma Thapa declares no relevant financial relationships with ineligible companies.

Disclosure: Utsav Shrestha declares no relevant financial relationships with ineligible companies.